Abstract
Histamine is considered a principle mediator of several physiological and pathological processes. It induces biological activities through differential expression of four types of histamine receptors (H1R, H2R, H3R and H4R). All the histamine receptors are the G protein-coupled receptor (GPCR) family, are expressed on several histamine responsive target tissues and cells, and suggest a potential role of histamine in cell proliferation, differentiation, hematopoiesis, embryonic development, regeneration, wound healing, aminergic neuron-transmission and several brain functions, secretion of pituitary hormones, regulation of gastrointestinal and circulatory functions, cardiovascular system, inflammatory reactions, immunomodulation, functioning of endocrine system and homeostasis. Since H4R has been discovered very recently and there is paucity of comprehensive literature covering new histamine receptors, their agonists/antagonists and role in various diseases. This has prompted a re-evaluation of the actions of histamine, suggesting a new potential for H4R-agonists/antagonists and a possible synergy between histamine receptors-agonists/antagonists in targeting various patho-physiological conditions. This chapter will highlight the biological and pharmacological characterization of histamine, histamine receptors, and their agonists/antagonists in various biomedical aspects.
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1 Introduction
Histamine (2-{imidazol-4-yl} ethylamine) is one of the monoamines and its name was coined after the Greek word for tissue histos. Histamine has a broad spectrum of activity in various physiological and pathological conditions including cell proliferation and differentiation, hematopoiesis, embryonic development, regeneration, wound healing, aminergic neuro transmission and numerous brain functions (sleep/nociception, food intake and aggressive behavior), secretion of pituitary hormones, regulation of gastrointestinal and circulatory functions, cardiovascular system (vasodilatation and blood pressure reduction), as well as inflammatory reactions, modulation of the immune response, endocrine function and homeostasis (Dy and Schneider 2004, Fumagalli et al. 2004, Haas and Panula 2003, Higuchi et al. 1999, Jutel et al. 2002, Schneider et al. 2002, Shahid et al. 2009, Yokoyama 2001). Histamine is probably one of the earliest known “phlogistic” mediators, and even one of the most intensely studied molecules in biological systems (Shahid et al. 2009). It was synthesized in 1907 and characterized in 1910 as a substance (“beta-1”), owing to its significant competence to constrict guinea pig ileum, and its cogent vasodepressor action. However, it took 17 years to demonstrate its presence in normal tissues. The relationship between histamine and anaphylactic reactions was made soon after that in 1929. Histamine was identified as a mediator of anaphylactic reaction in 1932, whereas its connection to mast cells was not made until 1952, and its connection to basophils in 1972 (Shahid et al. 2009). The search for compounds to neutralize the pathological effects of histamine began at the Pasteur Institute in Paris during the 1930s, and these compounds were found to partially block the effects of histamine based on the ethylenediamine structure. The first antihistamine compound was the adrenolytic benzodioxan, piperoxan (933F), reported by Ungar, Parrot and Bovet in 1937 and was shown to block the effect of histamine on the guinea-pig ileum, structurally related to aryl ethers such as the thymol ether (929F) (Bouvet and Staub 1937, Parsons and Ganellin 2006). This antihistamine compound proved to be too toxic for clinical development. However, the replacement of ether oxygen by an amino group led to the discovery of aniline ethylene diamine derivatives. For his research on antihistamines and curare, Bovet was awarded the Nobel Prize in 1957 (Shahid et al. 2009). The significant role of histamine in allergic reactions was further verified by a series of compounds with antihistamine activity which protected guinea pigs from anaphylaxis. However, the clinical use of these compounds in humans was deferred due to their toxicity (Bouvet and Staub 1937). The first antihistamine, Antergan™ (phenbenzamine, RP 2339) used in humans, was subsequently replaced by Neoantergan™ (mepyramine, pyrilamine, RP 2786), which is still in use to counteract the uncomfortable effects of histamine release in the skin. Many other antihistamines such as diphenhydramine (Benadryl™), tripelennamine, chlorpheniramine and promethazine are also used in similar manner to counteract the adverse effects of histamine (Parsons and Ganellin 2006). Since 1945, these antihistamines have been widely used in the treatment of various allergic diseases such as hay fever, urticaria, and allergic rhinitis. However, the side effect of sedation is a drawback to their use. On the other hand, another side effect allowed the use of antihistamines such as cyclizine (Marzine™) and diphenhydramine in the form of its 8-chlorotheophyllinate (Dramamine™) as antiemetics for travel sickness (Shahid et al. 2009). By 1950 there were 20 compounds available to block the effects of histamine, but advances in histamine receptor (H1R – H4R) knowledge has led to further pharmaceutical developments (Shahid et al. 2009). All these four receptors are members of the 7-transmembrane (heptahelical) spanning family of receptors, are G protein-coupled (GPCR), and are expressed on various histamine responsive target tissues and cells and suggest an important critical role of histamine in many diseases (Dy and Schneider 2004, Jutel et al. 2002, MacGlashan 2003, Parsons Ganellin 2006, Schneider et al. 2002). The antagonists for H1- and H2-receptors are used extensively in clinical medicine. H4R has been discovered very recently and there is paucity of comprehensive literature covering new histamine receptors and their agonists/antagonists. This chapter will highlight the biological and pharmacological characterization of histamine; histamine receptors (H1R – H4R); their agonists/antagonists; and their cellular distribution, functional characterization, structural biology, and signaling mechanisms; non-classical histamine-binding sites such as cytochrome P450; and histamine transporters.
2 Histamine Receptors
Histamine is an important biogenic amine and has multiple effects that are mediated through specific surface receptors on specific target cells. Four types of histamine receptors have now been identified. In 1966, histamine receptors were first differentiated into H1 and H2 (Ash and Schild 1966), and it was reported that some responses to histamine were inhibited by low doses of mepyramine (pyrilamine), whereas others were unsympathetic. In 1999, a third histamine receptor subtype was cloned and termed as H3 (Lovenberg et al. 1999). Subsequently in 2000, the fourth histamine receptor subtype was reported which was termed as H4 (Oda et al. 2000) and introduced a significant chapter in the story of histamine effects.
2.1 Histamine H1-Receptor
2.1.1 Cellular Distribution and Functional Characterization
In different mammalian tissues, the study of the distribution of histamine H1-receptors (H1Rs) has been significantly helped by the development of specific radioligands for this subtype (Shahid et al. 2009). In 1997, [3H]mepyramine a selective radioligand was developed (Table 4.1) (Hill et al. 1977), and since then it has been used to identify H1-receptors in a wide variety of tissues such as gastrointestinal tract, central nervous system, airways and vascular smooth muscle cells, mammalian brain, hepatocytes, nerve cells, endothelial cells, chondrocytes, monocytes, neutrophils, dendritic cells, T and B lymphocytes (Table 4.2), the cardiovascular system and genitourinary system, endothelial cells and adrenal medulla (Shahid et al. 2009). In many pathological processes of allergy, including allergenic rhinitis, atopic dermatitis, conjunctivitis, urticaria, asthma, and anaphylaxis, H1-receptors are involved. The receptors also mediate bronchoconstriction and enhanced vascular permeability in the lung (Haas and Panula 2003, Smit et al. 1999, Togias 2003). It has been noticed that [3H]mepyramine binds to secondary non-H1-receptor sites in various tissues and cells (Arias-Montano and Young 1993, Dickenson and Hill 1994, Leurs et al. 1995a). In addition to [3H]mepyramine, which predominantly binds to a protein homologous with debrisoquine 4-hydroxylase cytochrome P450 in rat liver (Fukui et al. 1990), this nonspecific binding can be blocked by quinine. This investigation led to the demonstration that quinine may be used to block binding to other lower affinity sites (Liu et al. 1992). However, it is clear that not all secondary binding sites for [3H]mepyramine are sensitive to inhibition by quinine. Thus, in DDT1MF-2 cells, a 38–40 kDa protein has been isolated, which binds H1R antagonists with KD values in the micromolar range but which is not sensitive to inhibition by quinine. Nevertheless, DDT1MF-2 cells can be shown to additionally possess [3H]mepyramine binding sites that have the characteristics of H1R (i.e., KD values in the nanomolar range) and to mediate functional responses, which are clearly produced by histamine H1R activation (Hill et al. 1997).
Furthermore, H1R is also responsible for changes in vascular permeability as a result of endothelial cell contraction (Meyrick and Brigham 1983, Svensjo and Grega 1986); in synthesis of prostacyclin (Carter et al. 1988, McIntyre et al. 1985); in platelet-activating factor synthesis (McIntyre et al. 1985); in release of Von Willebrand factor (Hamilton and Sims 1987), and in nitric oxide release (Van de Voorde and Leusen 1993). H1R on human T lymphocytes has been characterized by use of [125I]iodobolpyramine (Shahid et al. 2009, Villemain et al. 1990) (see also Table 4.1). H1R-deficient mice display both strong systemic T-cell and efficient B-cell responses to antigen (Bryce et al. 2006). H1R has also been demonstrated to increase (Ca2+)i (Kitamura et al. 1996). The relationship of H1Rs to adrenal medulla which elicits the release of catecholamines has been established many years ago (Noble et al. 1988, Livett and Marley 1986). Thus, histamine can stimulate the release of both adrenaline and noradrenaline (Livett and Marley 1986), and also induce phosphorylation of the catecholamine biosynthesis enzyme tyrosine hydroxylase by a mechanism which mediates release of intracellular calcium from cultured bovine adrenal chromaffin cells (Bunn et al. 1995). Histaminergic effects cause release of leucine- and methionine- enkephalin (Bommer et al. 1987) and a marked increase in mRNA-encoding proenkephalin A after prolonged exposure (Bommer et al. 1987, Wan et al. 1989). Its negative inotropic effects have been observed in human atrial myocardium and also in guinea pig ventricle (Genovese et al. 1988, Guo et al. 1984). Genovese et al. (1988) suggested that the negative inotropic response to histamine in human myocardium is associated with inhibitory effects on heart rate. This can be unmasked when the positive responses of histamine on the heart rate, and force of contraction (due to histamine H2-receptors) are mediated through conjoint administration of adenosine or adenosine A1-receptor agonists. However, histamine produces a positive inotropic effect in guinea pig left atria and rabbit papillary muscle by a specific mechanism which is not related to a rise in adenosine 3c, 5c-cyclic monophosphate (cAMP) levels (Hattori et al. 1988a,b, Shahid et al. 2009). The distribution of H1Rs in mammalian brain shows higher densities in neocortex, hippocampus, nucleus accumbent, thalamus, and posterior hypothalamus (Schwartz et al. 1991), however, cerebellum and basal ganglia have lower densities (Shahid et al. 2009, Yanai et al. 1992). The distribution of H1Rs in rat and guinea pig is very similar (Ruat and Schwartz 1989, Shahid et al. 2009). H1-receptor binding sites and mRNA levels were overlapped in most areas of brain except in hippocampus and cerebellum in which the inconsistency is mostly to reflect the presence of exuberance H1Rs in dendrites of pyramidal and Purkinje cells (Traiffort et al. 1994). The activation of H1R inhibits the firing and hyperpolarization in hippocampal neurons (Haas 1981) and also an apamine sensitive outward current in olfactory bulb interneurons (Jahn et al. 1995), and these effects are mostly generated by intracellular Ca2+ release. However, H1R excite various notable factors such as vegetative ganglia (Christian et al. 1989), hypothalamic supraoptic (Hill et al. 1997), brainstem (Khateb et al. 1990), thalamic (McCormick and Williamson 1991), and human cortical neurons (Reiner and Kamondi 1994) through a block of potassium conductance. Histaprodifens are very potent H1R agonists and are more effective than histamine in activating H1R (Elz et al. 2000).
The functional characterization of H1R has benefited from the use of many potent and specific antagonists (see Table 4.1) (Shahid et al. 2009, Sharma and Hamelin 2003). H1-receptor antagonists were developed initially as the anti-allergic drugs with the known side effect of sedation due to the disturbance of circadian rhythms and locomotor activities as well as the impairment of the exploratory behavior by histamine in the brain. Later the so-called “non-sedating” H1 antagonists which cannot cross the blood-brain barrier were designed (Shahid et al. 2009). Some anti-inflammatory effects of H1R antagonists at high doses could be non-specific because of histamine and other inflammatory mediators like leukotriene and platelet activating factors released from basophils in response to certain H1Rs antagonists (Shahid et al. 2009). Bordetella pertussis-induced histamine sensitization (Bphs) controls Bordetella pertussis toxin (PTX)-induced vasoactive amine sensitization elicited by histamine (VAASH) and has been established an important role of histamine in autoimmunity. The congenic mapping links Bphs to the histamine H1 receptor gene (Hrh1/H1R) and that H1R differs at three amino acid residues in VAASH-susceptible and -resistant mice. Hrh1–/– mice are protected from VAASH, which can be restored by genetic complementation with a susceptible Bphs/Hrh1 allele, and experimental allergic encephalomyelitis and autoimmune orchitis due to immune deviation. Thus, natural alleles of Hrh1 control both the autoimmune T cells and vascular responses regulated by histamine after PTX sensitization. The exact mechanism through which this effect occurs remains unclear and its clinical relevance is still uncertain (Ma et al. 2002). The chemical structure of specific H1R-antagonists and agonists are shown in Figs. 4.1 and 4.2.
2.1.2 Structural Biology of Receptor
H1 receptors have been cloned from cows, rats, guinea pigs and also from humans. The H1 receptor contains 486, 488 or 487 amino acids in rat, mouse and humans, respectively. It contains the typical properties of G protein coupled receptor (GPCR), namely, seven transmembrane domains of 20–25 amino acids predicted to form an α-helice which spans the plasma membrane and an extra cellular NH2 terminal domain with glycosylation site. H1R is encoded by a single exon gene that is located on the distal short arm of chromosome 3p25 in humans see in Fig. 4.1 and chromosome 6 in mice. Histamine binds to aspartate residues in the transmembrane domain 3 of the H1-receptor, and to asparagine + lysine residues within the transmembrane domain 5 (Shahid et al. 2009). Its structural studies done by photoaffinity binding properties using [125I]iodoazidophenpyramine (Table 4.1) and subsequent sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE) analysis demonstrated that the H1-receptor protein (molecular weight 56 kDa) is found under reducing conditions in the brain of rat, guinea pig, and mouse (Ruat et al. 1990a, Shahid et al. 2009).
Similar studies have also been done by using photoaffinity ligand [3H] azidobenzamide in bovine adrenal medullar membranes and found labeled peptides in the size range 53–58 kDa (Yamashita et al. 1991). In guinea pig heart, the specifically labeled H1R with [125I]iodoazidophenpyramine was found to contain substantially higher molecular weight, while there was no obvious difference in the characteristics of the H1R in tissues (Table 4.1) (Ruat et al. 1990b). In 1991, H1R was cloned from the bovine adrenal medulla by expression cloning in the Xenopus oocyte system. Interestingly, 491 amino acid protein with a calculated molecular weight of 56 kDa was represented by the deduced amino acid sequence (Yamashita et al. 1991); this protein has the seven transmembrane domains expected of a G-protein coupled receptor (GPCR) and contains N-terminal glycosylation sites. The main feature of the proposed H1R structure is the very large 3rd intracellular loop with 212 amino acids and relatively short intracellular C terminal tail with 17 amino acids. The availability of the bovine sequence and lack of introns has enabled the H1-receptor to be cloned from several species including rat (Fujimoto et al. 1993), guinea pig (Horio et al. 1993), mouse (Inove et al. 1996), and human (De Backer et al. 1993, Smit et al. 1996). The human H1-receptor gene has now been localized to chromosome 3 bands 3p14–p21 (Table 4.2). These clones should be regarded as true species homologues of the H1-receptor, while there are notable variations amongst them in some antagonist potencies (Shahid et al. 2009). Nevertheless, it is clear that the stereoisomers of chlorpheniramine show marked differences between species. For example, the guinea pig H1-receptor has a KD of 0.9 nM for (1)-chlorpheniramine, whereas for the rat H1-receptor, the value is nearly 8 nM (Shahid et al. 2009). Similar variations for chlorpheniramine and other compounds (mepyramine and triprolidine) have been shown in guinea pig and rat brain, respectively (Shahid et al. 2009). The species differences may explain why compound [125I]iodobolpyramine can label guinea pig CNS H1-receptors, but it is unable to identify H1Rs in the brain of rat (Shahid et al. 2009). In brain membranes of both guinea pig and rat the native H1-receptor protein has been solubilized (Toll and Snyder 1982, Treherne and Young 1988), and the solubilized receptor retains similar differences in H1-antagonist potency for (1)-chlorpheniramine as that detected in membranes (Toll and Snyder 1982). It is important to note that mepyramine seems to be potent antagonist of the recombinant rat H1-receptor (i.e. expressed in C6 cells) than of the native histamine H1-receptor in the brain membrane of rat (Shahid et al. 2009).
In addition, the recombinant studies performed in rat C6 cells (Fujimoto et al. 1993) are complicated by the presence of a low level of endogenous histamine H1-receptors (H1Rs) (Peakman and Hill 1994), but in the functional studies in untransfected C6 cells, a high affinity for mepyramine (KD 51 nM) has been deduced (Peakman and Hill 1994). The amino acid sequence alignment of the cloned histamine H1- and H2-receptors led to the suggestion that the third and fifth transmembrane domains (TM3 and TM5 respectively) of receptor proteins are responsible for histamine binding (Birdsall 1991, Timmerman 1992). In third transmembrane (TM3) of the human H1-receptor, Aspartate (107) that is conserved in entire aminergic receptors, has appeared to be essential for the histamine binding, and also H1-receptor antagonists to the H1-receptor (Ohta et al. 1994). In H1-receptor, the amino acid residues corresponding to Asparagine (198) and Threonine (194) are in corresponding positions in 5th transmembrane domain (TM5) of the human H1-receptor, while the substitution of an Alanine for Threonine (194) did not influence the binding properties of either agonist or antagonist (Moguilevsky et al. 1995, Ohta et al. 1994). However, the substitution of Alanine (198) for Asparagine (198) decreased agonist affinity, while the affinity of antagonist remained unchanged (Moguilevsky et al. 1995, Ohta et al. 1994). Similar results have been seen in the mutations to the corresponding residues Threonine (203) and Asparagine (207) in the guinea pig-H1R sequence (Leurs et al. 1994a). In addition to these mutations 2-methylhistamine is affected by the Asparagine (207) Alanine mutation, and H1-selective agonists 2-thiazolylethylamine, 2-pyridylethylamine, and 2-(3-bromophenyl) histamine are much less influenced through this mutation (Leurs et al. 1995b). This suggested that Asparagine (207) interacts with the Nt-nitrogen of histamine imidazole ring.
However, it has been shown that Lysine(200) interacts with the Np-nitrogen of histamine ring, and that it is important for the activation of the H1R by histamine and the nonimidazole agonist, 2-pyridylethylamine (Shahid et al. 2009). Furthermore, Leurs et al. (1995b) has demonstrated that the Lysine(200) Alanine mutation did not alter the binding affinity of 2-pyridylethylamine to H1R of guinea pig. Thus, the studies on the organization, genomic structure and promoter function of the human H1R revealed a 5.8 kb intron in the 50 flanking region of this gene, different binding sites for various transcription factors, and the absence of TATA and CAAT sequences at the appropriate locations (De Backer et al. 1998).
2.1.3 Signaling Mechanisms
H1-receptor is a Gαq/11-coupled protein with a very large third intracellular loop and a relatively short C-terminal tail see in Fig. 4.3 (Shahid et al. 2009). The main signal induced by ligand binding is the activation of phospholipase C-generating inositol 1, 4, 5-triphosphate and 1, 2-diacylglycerol (DAC) leading to increased cytosolic Ca2+ (Shahid et al. 2009). The enhanced intracellular Ca2+ levels appear to account for the different pharmacological properties promoted through the receptor including nitric oxide (NO) production, liberation of arachidonic acid from phospholipids, contraction of smooth muscles, dilatation of arterioles and capillaries, vascular permeability in vessels as well as stimulation of afferent neurons, and increased cAMP, and also cGMP levels (Bakker et al. 2002) (see also Table 4.2). This receptor also stimulates nuclear factor kappa B (NFκB) by Gαq/11 and Gβγ upon binding of agonist, while stimulation of NFκB occurs only via Gβγ leading to (pro)inflammatory mediators (Bakker et al. 2001). In a number of tissues and cell types H1R-mediated increases in either inositol phosphate accumulation or intracellular calcium mobilization has been described extensively and further details are provided in several comprehensive reviews (Hill and Donaldson 1992, Leurs et al. 1994b). In Chinese hamster ovary (CHO) cells Ca2+ mobilization and [3H]inositol phosphate accumulation has been observed due to stimulation by histamine when CHO cells are transfected with H1R-complementary deoxyribonucleic acid (cDNA) of the human, bovine, and guinea pig origin (Leurs et al. 1994c, Megson et al. 1995).
It is important to note that in some tissues histamine can stimulate inositol phospholipid hydrolysis independently of H1Rs. Thus, in the longitudinal smooth muscle of guinea pig ileum and neonatal rat brain (Claro et al. 1987), a component can be identified in response to histamine that is resistant to inhibition by H1R-antagonists. It is yet to be established whether these effects are due to “tyramine-like” effects of histamine on neurotransmitter release or direct effects of histamine on the associated G-proteins (Bailey et al. 1987, Seifert et al. 1994). In addition to well known effects on the inositol phospholipid signal transduction systems, several other signal transduction pathways can lead to stimulation of H1R and seem to be secondary to changes in intracellular Ca2+concentration or protein kinase C (PKC) activation. Thus, nitric oxide synthase activity (via a Ca2+/calmodulin-dependent pathway), and subsequent stimulation of soluble guanylyl cyclase in a wide variety of various cell types can be activated by histamine (Hattori et al. 1990, Leurs et al. 1991, Schmidt et al. 1990, Yuan et al. 1993). The H1R can stimulate the arachidonic acid release and arachidonic acid metabolite synthesis such as prostacyclin and thromboxane (Muriyama et al. 1990). It has been demonstrated that the histamine-stimulated release of arachidonic acid is partially inhibited (~40%) by pertussis toxin, when CHO-K1 cells transfected with the guinea pig H1R and the same response is also shown in HeLa cell possessing a native H1R to resist pertussis toxin treatment (Shahid et al. 2009). The substantial changes in the intracellular levels of cAMP can be produced by H1-receptor activation, but in most tissues, H1R activation does not stimulate adenylyl cyclase directly, and acts for the amplification of cAMP responses to histamine H2 receptor, adenosine A2 receptor, and also vasoactive intestinal polypeptide receptors (Donaldson et al. 1989, Garbarg and Schwartz 1988, Marley et al. 1991). The role of both intracellular Ca2+ ions and protein kinase C has been demonstrated in various cases in this augmentation response (Garbarg and Schwartz 1988). H1R stimulation can also lead to both cAMP responses and to an increase of forskolin-activated cAMP formation when CHO cells are transfected with the bovine or guinea pig H1R (Sanderson et al. 1996, Shahid et al. 2009).
2.2 Histamine H2-Receptor
2.2.1 Cellular Distribution and Functional Characterization
The H2R is located on chromosome 5 in humans. Similar to what has been demonstrated for H1R, the histamine binds to transmembrane (TM) domains 3 (aspartate) and TM 5 (threonine and aspartate). The short 3rd intra-cellular loop and the long C-terminal tail are also a feature of H2R subtype, and the rat N-terminal extracellular tail has N-linked glycosylation sites (Del Valle and Gantz 1997). Similar to H1R, H2R is expressed in different cell types (Table 4.2) (Shahid et al. 2009). It has been documented that H2R is mostly involved in suppressive activities of histamine, while stimulative effects are mediated through H1R. The activation of H2R regulates various functions of histamine including heart contraction, gastric acid secretion, cell proliferation, differentiation and immune response. H2R antagonists, such as zolantidine, are effective in the treatment of stomach and duodenal ulcers and the clinical potency relates to the suppressive effect of these drugs on the secretion of stomach acids (Dy and Schneider 2004, Shahid et al. 2009).
Hill (1990) designed a study to map the distribution of H2Rs by using radiolabeled H2R-antagonists, and achieved more affinity with [3H] titotidine (Table 4.1) for the H2R in guinea pig brain, lung parenchyma, and CHO-K1 cells transfected with the human H2-receptor cDNA (Gajtkowski et al. 1983, Gantz et al. 1991a, Sterk et al. 1986), but it was not successful in the studies of rat brain (Maayani et al. 1982). The most useful H2R-radioligand is [125I]iodoaminopotentidine, which has high affinity (KD 50.3 nM) for the H2R in brain membranes (Table 4.1) (Hirschfeld et al. 1992, Traiffort et al. 1992a,b) and also in CHO-K1 cells expressing the cloned rat H2R (Traiffort et al. 1992b). This compound has also been used for autoradiographic mapping of H2Rs in the brain of mammal (Traiffort et al. 1992a). [125I]iodoaminopotentidine is also a useful H2R-radioligand (Table 4.1), which was used to map the distribution of H2Rs in human brain with highest densities in the basal ganglia, hippocampus, amygdale, and cerebral cortex, and also lowest densities were identified in cerebellum and hypothalamus (Traiffort et al. 1992a). In guinea pig brain, a similar distribution has been observed (Shahid et al. 2009). Irreversible labeling has also been successfully accomplished by [125I]iodoazidopotentidine (Table 4.1) (Shahid et al. 2009). H2R-stimulated cyclic AMP accumulation or adenylyl cyclase activity in Fig. 4.3 has been shown in various tissues including gastric cells, cardic tissue and brain (Al-Gadi and Hill 1985, 1987) and gastric cells (Johnson 1982). The potent effect of H2Rs have been demonstrated on gastric acid secretion and the inhibition of this secretory process through H2R antagonists had provided evidence for physiological role of histamine in gastric acid secretion (Black and Shankley 1985, Soll and Berglindh 1987). In cardiac tissues of most animal species, high concentrations of histamine were present which can mediate positive chronotropic and inotropic impacts on atrial or ventricular tissues by H2R stimulation (Hescheler et al. 1987, Levi and Alloatti 1988). Also H2R-mediated smooth muscle relaxation has been documented in vascular smooth muscle, uterine muscle and in airways (Foreman et al. 1985, Ottosson et al. 1989).
Hill (1990) had demonstrated that the effects of H2Rs can inhibit a variety of functions within the immune system. H2Rs have been shown to negatively regulate the release of histamine in basophils and mast cells (Plaut and Lichtenstein 1982, Ting et al. 1980). The inhibition of antibody synthesis, T-cell proliferation, cell-mediated cytolysis, and cytokine production were point to the evidence of H2Rs on lymphocytes (Banu Watanabe 1999, Jutel et al. 2001, Melmon and Khan 1987). The chemical structure of specific H2R-antagonist and -agonists are shown in Figs. 4.4 and 4.5.
2.2.2 Structural Biology of Receptor
The structural studies of H2R have been conducted using [125I]iodoazidopotentidine and sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) and it was suggested that the H2R in guinea pig hippocampus and striatum has a molecular weight of 59 kDa (Shahid et al. 2009). However, comparison with the calculated molecular weights (40.2–40.5 kDa) for the cloned H2Rs indicates that the native H2R in the brain of guinea pig was glycosylated. The cloned H2R proteins possess N-glycosylation sites in the N-terminus region (Gantz et al. 1991b, Ruat et al. 1991, Traiffort et al. 1995). Fukushima et al. (1995) has suggested that removal of these glycosylation sites by site-directed mutagenesis showed that N-glycosylation of the H2R is not essential for cell surface localization, ligand binding, or coupling via Gs to adenylyl cyclase. Gantz and colleagues for the first time successfully cloned H2R using the polymerase chain reaction to amplify a partial length H2R sequence from canine gastric parietal cDNA using degenerate oligonucleotide primers and this sequence was then used to identify a full length H2R clone following screening of a canine genomic library (Shahid et al. 2009). Following this cloning, many researchers have cloned the rat, human, guinea pig, and mouse H2Rs (Kobayashi et al. 1996, Shahid et al. 2009). These intronless gene (DNA) sequences encode 359 amino acids for canine, human, guinea pig or 358 amino acids for rat receptor protein which has the general properties of a G-protein-coupled receptor (GPCR) (Table 4.2). The radioligand binding studies using [125I]iodoaminopotentidine were attempted to show the expression of rat and human H2R proteins in CHO cells and revealed the expected pharmacological specificity as shown in Table 4.1 (Shahid et al. 2009). Chromosomal mapping studies have demonstrated that the H2R gene is localized to human chromosome 5 (Shahid et al. 2009). Birdsall (1991) has compared H2R sequence with other biogenic amine G-protein coupled receptors (GPCRs), and demonstrated that an aspartate in transmembrane (TM) domain 3 and an aspartate and threonine residue in TM 5 were more responsible for histamine binding. Replacement of aspartate (98) by an asparagine residue in the canine H2-receptor results in a receptor that does not bind the antagonist tiotidine and does not stimulate cAMP accumulation in response to histamine (Gantz et al. 1992, Hill et al. 1997). On changing the aspirate (186) residue of TM 5 to an alanine residue, there occurs complete loss of the antagonist titotidine binding without affecting the EC 50 for cAMP formation in response to histamine stimulation. Changing the threonine (190) residue to an alanine residue, resulted in a lower KD for titotidine antagonist and also a reduction in both the histamine EC 50 value and maximal cAMP response (Gantz et al. 1992). Mutation of Asp (186) and Gly (187) residue in the canine histamine H2-receptor to Ala (186) and Ser (187) residue produces a bifunctional receptor, which can be activated through adrenaline, and inhibited via both cimetidine and propranolol (Delvalle et al. 1995). These results indicate that pharmacological specificity of the H2R resides in only limited key amino acid residues.
2.2.3 Signaling Mechanisms
H2R is coupled both to adenylate cyclase and phosphoinositide second messenger systems via separate GTP-dependent mechanisms. Receptor binding stimulates activation of c-Fos, c-Jun, protein kinase C (PKC) and p70 S6 kinase (Shahid et al. 2009) see in Fig. 4.3. Histamine was shown to be a highly potent stimulant of cAMP accumulation in various cells, and H2R-dependent impacts of histamine were predominantly mediated through cAMP, particularly those of central nervous system (CNS) origin (Shahid et al. 2009). Thus, H2R-mediated impacts on cAMP accumulation have been well documented and demonstrated in brain slices, gastric mucosa, fat cells, cardiac myocytes, vascular smooth muscle, basophils and neutrophils (Batzri et al. 1982, Gespach and Abita 1982, Shahid et al. 2009). In addition, H2R-mediated cAMP accumulation had been observed in Chinese hamster ovary (CHO) cells transfected with the rat, canine, or human H2R cDNA (Leurs et al. 1994, Shahid et al. 2009). In both brain and cardiac muscle membranes, the direct stimulation of adenylyl cyclase activity in cell free preparations had been detected (Newton et al. 1982, Olianas et al. 1984).
However, Hill (1990) has suggested used for caution in interpretation of receptor characterization studies using histamine-stimulated adenylyl cyclase activity alone. A most striking feature of studies of H2R-stimulated adenylyl cyclase activity in membrane preparations was the potent antagonism demonstrated with certain neuroleptics and antidepressants (Green 1983). In intact cellular systems, most of the neuroleptics and antidepressants were approximately 2 orders of magnitude weaker as antagonists of histamine-stimulated cAMP accumulation (Kamba and Richelson 1983, Kitbunnadaj 2005). One highly potential explanation for these variations resides within the buffer systems used for the cell-free adenylyl cyclase assays, and some differences in potency of some antidepressants and neuroleptics have been demonstrated when membrane binding of H2Rs has been evaluated using [125I]iodoaminopotentidine (Table 4.1) (Shahid et al. 2009). However, the variations observed in the Ki values deduced from studies of ligand binding in different buffers are not as large as the variations in KB values obtained from functional studies. For example, in the case of amitriptyline, no difference was observed in binding affinity in Krebs and Tris buffers (Traiffort et al. 1991). In addition to Gs-coupling to adenylyl cyclase, H2Rs are coupled to other signaling systems also. For example, H2R stimulation has been demonstrated to enhance the intracellular free concentration of calcium (Ca2+) ions in gastric parietal cells (Chew and Petropoulos 1991, Delvalle et al. 1992a). In some cell systems, Gαq coupling to PLC and intracellular Ca2+ had been demonstrated (Table 4.2). In HL-60 cells, a similar calcium (Ca2+) response to H2R stimulation had been demonstrated (Seifert et al. 1992), and same case was observed in hepatoma-derived cells transfected with the canine H2Rs cDNA (Delvalle et al. 1992b). The influence on [Ca2+]i was accompanied by both an increase in inositol trisphosphate accumulation and a stimulation of cAMP accumulation in these cells (Shahid et al. 2009). Both the H2R-stimulated calcium and inositol trisphosphate responses were inhibited by cholera toxin treatment, whereas cholera toxin produced the expected increase in cAMP levels (Shahid et al. 2009). H2Rs release Ca2+ from intracellular calcium stores in single parietal cells (Negulescu and Machen 1988) and no effect of H2R agonists was observed on intracellular calcium levels or inositol phosphate accumulation in CHO cells transfected with the H2R of human. Thus, the effect of H2R stimulation on intracellular Ca2+ signaling may be highly cell-specific (Shahid et al. 2009).
The stimulation of H2R produces both inhibition of P2u-receptor-mediated arachidonic acid release and an increase in cAMP accumulation in CHO cells transfected with the rat H2R (Traiffort et al. 1992a). Traiffort et al. (1992b) has demonstrated that the effect on phospholipase A2 activity (i.e., arachidonic acid release) is not mimicked by forskolin, PGE1, or 8-bromo-cAMP, suggesting a mechanism of activation that is independent of cAMP-mediated protein kinase A activity. However, inhibitory effects of H2R stimulation were observed on phospholipase A2 activity in CHO cells transfected with the human H2R. Thus, these cAMP-independent effects might depend on the level of receptor expression or subtle differences between clonal cell lines (Shahid et al. 2009).
2.3 Histamine H3-Receptor
2.3.1 Cellular Distribution and Functional Characterization
The neurotransmitter function of histamine was established with the discovery of the H3R. This involves brain functions, as well as the peripheral effect of histamine on mast cells via H3Rs, that might be connected to a local neuron-mast cell interaction (Dimitriadou et al. 1994). Its involvement in cognition, sleep-wake status, energy homeostatic regulation and inflammation led to research as therapeutic approaches mainly for central diseases (Hancock and Brune 2005, Passani et al. 2004). A recent study reported that H3R is presynaptically located as on autoreceptor controlling the synthesis and release of histamine (Leurs et al. 2005). This H3-autoreceptor activation stimulates the negative feedback mechanism that reduces central histaminergic activity (Teuscher et al. 2007). H3R’s heterogeneity in binding and its functional studies has been well documented, which suggests more than one H3R subtype. This has been confirmed by demonstration of several H3R variants, generated from the complex H3R gene by alternative splicing. The three functional isoforms have been found in the rat, and they all vary in length of the 3rd intracellular loop, their distinct central nervous system (CNS) localization, and differential coupling to adenylate cyclase and MAPK signaling. Similar results were obtained for humans (Cogé et al. 2001, Drutel et al. 2001, Wellendorph et al. 2002).
Thus, numerous isoforms found in different species and different tissues lead to the assumption that fine-tuning of signaling may be controlled via receptor oligomerization or formation of isoforms (Bongers et al. 2007).
H3R is anatomically localized primarily to the CNS with prominent expression in basal ganglia, cortex hippocampus and striatal area. In the periphery, H3R can be found with low density in gastrointestinal, bronchial and cardiovascular system (Stark 2007). The high apparent affinity of R-(α)-methylhistamine for the H3R has enabled the use of this compound as a radiolabeled probe (Table 4.1) (Arrang et al. 1987). In rat cerebral cortical membranes, this compound (R-(α)-methylhistamine) has been used to identify a single binding site, which has the important pharmacological characteristics of the H3R (Arrang et al. 1990). In rat brain membranes, [3H]R-(α)-methylhistamine binds with high affinity (KD 50.3 nM), although its binding capacity is low (~30 fmol/mg protein) (Shahid et al. 2009). The autoradiographic studies with [3H]R-(α)-methylhistamine have described the presence of specific thioperamide-inhibitable binding in several rat brain regions, especially cerebral cortex, striatum, hippocampus, olfactory nucleus, and the bed nuclei of the stria terminalis, which receive ascending histaminergic projections from the magnocellular nuclei of the posterior hypothalamus (Pollard et al. 1993, Shahid et al. 2009). In human brain and the brain of nonhuman primates, the H3Rs have also been visualized (Martinez-Mir et al. 1990). H3R binding has been characterized using [3H]R-(α)-methylhistamine in guinea pig lung (Arrang et al. 1987), guinea pig cerebral cortical membranes (Kilpatrick and Michel 1991), guinea pig intestine and guinea pig pancreas (Korte et al. 1990). Nα-methylhistamine has been useful as a radiolabeled probe for the H3R (Table 4.1). The relative agonist activity of Nα-methylhistamine (with respect to histamine) was significantly similar for all three histamine receptor (HRs) subtypes, but the binding affinity of histamine and Nα-methylhistamine for the H3R was several orders of magnitude higher than for either H1- or H2-receptors (Shahid et al. 2009). Nα-methylhistamine can identify high-affinity H3R sites in both rat and guinea pig brain (Clark and Hill 1995, Korte et al. 1990, West et al. 1990). The binding of H3-receptor-agonists to H3Rs in brain tissues was found to be regulated by guanine nucleotides, implying its relation to heterotrimeric G-proteins (Zweig et al. 1992). Also the binding of H3R agonists appears to be affected by several cations. For example magnesium (Mg2+) and sodium (Na+) ions inhibit [3H]R-(α)-methylhistamine binding in guinea pig and rat brain, and the presence of calcium (Ca2+) ions has been shown to reveal heterogeneity of agonist binding (Shahid et al. 2009). It is important to note that the inhibitory effect of sodium (Na2+) ions on agonist binding means higher Bmax values that were usually obtained in sodium-free Tris buffers compared with the Na/K phosphate buffers (Clark and Hill 1995). The multiple histamine H3R subtypes exist in rat brain (termed H3A and H3B) on the basis of [3H]N α-methylhistamine binding in rat cerebral cortical membranes in 50 mM Tris buffer (Table 4.1) (West et al. 1990). Based on these conditions, the selective histamine H3-antagonist thioperamide can discriminate two affinity-binding states (West et al. 1990). Heterogeneity of thioperamide binding is sodium (Na2+) ion concentration dependent or depends on guanine nucleotides within the incubation medium. Thus, in the presence of 100 mM sodium chloride, thioperamide binding conforms to a single binding isotherm, and H3R can exist in different conformations which thioperamide, but not agonists or other H3R-antagonists (clobenpropit) can discriminate. This suggests that the equilibrium between these conformations is altered by guanine nucleotides or sodium (Na2+) ions (Shahid et al. 2009). If this speculation is correct, it is likely that the different binding sites represented resting, active, or G-protein-coupled conformations of the H3R. Furthermore, if thioperamide preferentially binds to uncoupled receptors, then this compound should exhibit negative efficacy in functional assays. Radiolabeled H3R antagonist [125I]iodophenpropit, has been used to label histamine H3Rs in rat brain membranes (Table 4.1) (Jansen et al. 1992). The inhibition curves for iodophenpropit and thioperamide were consistent with interaction with a single binding site, but H3R agonists were found to be able to discriminate both high-[4 nM for R-(α)-methylhistamine] and low-[0.2 mM for R-(α)-methylhistamine] affinity binding sites (Jansen et al. 1992). [3H]GR16820 and [125I]iodoproxyfan have been useful as high-affinity radiolabeled H3R-antagonists (Brown et al. 1994, Ligneau et al. 1994). In rat striatum, in the IUPHAR classification of histamine receptors 267 guanine nucleotides such as guanosine 59O-(3-thiotriphosphate) (GTPgS), 40% of the binding sites exhibited a 40-fold lower affinity for H3-agonists, providing further evidence for a potential linkage of H3Rs to G-proteins (Shahid et al. 2009). In rat brain membranes, [3H]thioperamide and [3H]5-methylthioperamide, have both been used to label H3R. However, [3H]thioperamide was shown to bind additionally to low affinity, high-capacity, non H3R sites (Alves-Rodrigues et al. 1996). The localization of H3Rs is based on functional studies, primarily involving inhibition of neurotransmitter release. The H3R was first characterized as an auto receptor regulating histamine synthesis and release from rat cerebral hippocampus, cortex, and striatum. The H3R-mediated inhibition of histamine release has also been demonstrated in human cerebral cortex (Arrang et al. 1988). Differences in the distribution of H3R binding sites and the levels of histidine decarboxylase (an index of histaminergic nerve terminals) suggested at an early stage that H3Rs are not confined to histamine-containing neurons within the mammalian CNS (Van der Werf and Timmerman 1989). It has been demonstrated that H3Rs can regulate neurotransmitter release in mammalian brain as serotonergic, noradrenergic, cholinergic, and dopaminergic (Clapham and Kilpatrick 1992, Schlicker et al. 1989, 1992, 1993). H3R activation inhibits the firing of the histamine-neurons in the posterior hypothalamus by a mechanism different from auto-receptor functions found on other aminergic nuclei, and is presumably a block of Ca2+ current (Haas 1992). H3Rs were found to regulate the release of sympathetic neurotransmitters in guinea pig mesenteric artery, human saphenous vein, guinea pig atria, and human heart (Endou et al. 1994, Imamura et al. 1994, 1995, Ishikawa and Sperelakis 1987, Molderings et al. 1992).
An important inhibitory effect of H3R activation on release of neuropeptides (tachykinins or calcitonin gene-related peptide) from sensory C fibers has been reported from airways, meninges, skin, and heart (Ichinose et al. 1990, Imamura et al. 1996, Matsubara et al. 1992, Ohkubo and Shibata 1995). The modulation of acetylcholine, capsaicin, and substance P effects by H3Rs in isolated perfused rabbit lungs has also been reported (Delaunois et al. 1995). There is evidence that H3R activation can inhibit the release of neurotransmitters from nonadrenergic- noncholinergic nerves in guinea pig bronchioles and ileum (Burgaud and Oudart 1994, Taylor and Kilpatrick 1992). In guinea pig ileum, the H3R-antagonists betahistine and phenylbutanoylhistamine were much less potent as inhibitors of H3R-mediated effects on nonadrenergic-noncholinergic transmission than they were as antagonists of histamine release in rat cerebral cortex (Taylor and Kilpatrick 1992).
A similar low potency has been reported for betahistine and phenylbutanoyl (histamine antagonists) for antagonism of H3R-mediated [3H]acetylcholine release from rat entorhinal cortex (Clapham and Kilpatrick 1992), and antagonism of H3R-mediated 5-hydroxytryptamine release from porcine enterochromaffin cells (Schworer et al. 1994). These investigations provide support for the potential existence of distinct H3R subtypes. In addition, it has been shown that phenylbutanoylhistamine can inhibit [3H]acetylcholine release from rat entorhinal cortex slices, and synaptosomes by a nonhistamine receptor mechanism (Arrang et al. 1995). Therefore, the potency of phenylbutanoylhistamine as H3R-antagonist in those preparations can be highly underestimated because of the additional nonspecific activities of the drug (Arrang et al. 1995). The inhibitory effect of H3-receptor stimulation on 5-HT release from porcine enterochromaffin cells in strips of small intestine (Schworer et al. 1994) provides evidence for H3-receptors regulating secretory mechanisms in non-neuronal cells. Hence, it can be concluded that H3R may be present in gastric mast cells or enterochromaffin cells and exerts an inhibitory effect on histamine release and gastric acid secretion. In conscious dogs, H3R activation had been observed to inhibit gastric acid secretion (Soldani et al. 1993). The H3R relaxes rabbit middle cerebral artery by an endothelium-dependent pathway involving both nitric oxide and prostanoid release (Ea Kim and Oudart 1988). H3-receptor stimulation can activate adrenocorticotropic hormone release from the pituitary cell line AtT-20 (Clark et al. 1992). Therefore, H3R provides constitutive properties, which means part of the receptor population spontaneously undergoes allosteric transition leading to a conformation, to which G protein can bind, and also H3R-knock out mice manifest an obese phenotype (characterized by increased body weight, food intake, adiposity, and reduced energy expenditure) (Morisset et al. 2000, Rouleau et al. 2002). Recently, it has been observed that H3R expresses insulin and leptin resistance as well as a diminution of the energy homeostasis-associated genes UCP1 and UCP3 (Takahashi et al. 2002). The chemical structure of specific H3R-antagonists and -agonists are shown in Figs. 4.6 and 4.7.
2.3.2 Structural Biology of Receptor
H3R is G protein-coupled receptor (GPCR) and has been cloned (Shahid et al. 2009). Its gene consists of 4 exons spanning 5.5 kb on chromosome 20 (20q13.33) in humans (Table 4.2). Structural studies of H3R are very limited and there are only few reports on its purification studies. By using [3H]histamine as a radioligand, the solubilization of a H3R protein from bovine whole brain has been reported. Size-exclusion chromatography has revealed an apparent molecular mass of 220 kDa. However, because the solubilized receptor retained its guanine nucleotide sensitivity and it is likely that the molecular mass of 220 kDa represents a complex of receptor, G-protein, and digitonin (Shahid et al. 2009). Cherifi et al. (1992) have reported the solubilization (with Triton X-100) and purification of the H3-receptor protein from the human gastric tumoral cell line HGT-1. After gel filtration and sepharose-thioperamide affinity chromatography, protein has been purified with a molecular mass of approximately 70 kDa (see Table 4.2).
2.3.3 Signaling Mechanisms
The signal mechanisms used by the H3R remain largely subject to speculation, but there is increasing evidence to suggest that this receptor belongs to the G-protein-coupled receptors (Gi/o) (Table 4.2), and its activation leads to inhibition of cAMP formation, accumulation of Ca2+ and stimulation of mitogen-activated protein kinase (MAPK) pathway (Shahid et al. 2009), see Fig. 4.3. This evidence has been obtained from ligand-binding studies that involve the modulation by guanine nucleotides of H3R-agonist binding and inhibition of H3R-antagonist binding (Jansen et al. 1994, Shahid et al. 2009). The direct evidence for a functional H3R-G-protein linkage came from studies of [35S]GTPgS binding to rat cerebral cortical membranes (Clark and Hill 1996). In rat cerebral cortical membranes, the presence of H1R- and H2R-antagonists (0.1 mM mepyramine and 10 mM titotidine), and both R-(α)-methylhistamine and N-(α)-methylhistamine generated a concentration dependent stimulation of [35S]GTPgS binding (EC50 = 0.4 and 0.2 nM) (Clark and Hill 1996). Notably, this response was inhibited by pretreatment of membranes with pertussis toxin, implying a direct coupling to a Gi or Go protein (Clark and Hill 1996). The evidence of pertussis toxin-sensitive G-proteins in the response to H3R stimulation came from studies of H3R signaling in human and guinea pig heart (Shahid et al. 2009). H3R-activation appeared to lead to an inhibition of N-type Ca2+ channels responsible for voltage dependent release of noradrenaline in human and guinea pig heart, but several investigations have failed to demonstrate an inhibition of adenylyl cyclase activity in different tissues and cells, which suggest that H3Rs couple to Go proteins (Schlicker et al. 1991, Shahid et al. 2009).
2.4 Histamine H4-Receptor
2.4.1 Cellular Distribution and Functional Characterization
The discovery of the H4-receptor adds a new chapter to the histamine story. The H4R is preferentially expressed in intestinal tissue, spleen, thymus, medullary cells, bone marrow and peripheral hematopoietic cells, including eosinophils, basophils, mast cells, T lymphocytes, leukocytes and dendritic cells (Shahid et al. 2009). However, moderate positive signals have also been detected in brain, spleen, thymus, small intestine, colon, heart, liver and lung. Although expression studies did not demonstrate H4Rs in the central nervous system (CNS), in situ hybridization studies suggested evidence for their localization human brain in low density (Shahid et al. 2009). The relatively restricted expression of the H4R provides an important role in inflammation, hematopoiesis and immunity by the regulation of H4R expression via stimuli such as IFN, TNF-α and IL-6, IL-10, and IL-13. Basophils and mast cells express H4R-mRNA. The H4R mediates chemotaxis of mast cells and eosinophils as well as controls cytokine release from dendritic cells and T-cells (Shahid et al. 2009).
H4R participates along with the H2R, in the control of IL-16 release from human lymphocytes. The H4R selective antagonist might be useful as anti-inflammatory agents in asthma, arthritis, colitis and pruritis (Shahid et al. 2009). Antagonists, such as JNJ 7777120, have been shown to be effective in various model of inflammation. At this point, very little is known about the biological functions of H4R. There are few reports in the literature, providing evidence for its role in chemotactic activity in mast cells and eosinophils or control of IL-16 production by CD8+ lymphocytes (Shahid et al. 2009). A recent study showed the role of H4R in mast cell, eosinophil, and T cell function, as well as the effects of its antagonist, JNJ 7777120, in a mouse peritonitis model pointing to a more general role for H4R in inflammation. In many diseases such as allergic rhinitis, asthma, and rheumatoid arthritis, conditions where eosinophils and mast cells are involved, H4R antagonists have potential therapeutic utility (Thurmond et al. 2004). The discovery of H4R and its emerging role in inflammation had spurred new interest in the functions of histamine in inflammation, allergy and autoimmune diseases. Early results in animal models suggest that H4R antagonists may have utility in treating various conditions in humans, in particular, in diseases in which histamine is known to be present and H1R antagonists are not clinically effective (Thurmond et al. 2008). Obviously, a better functional characterization of H4R will be possible by new, specific tools, such as the recently developed potent and selective non-imidazol H4R antagonist (Thurmond et al. 2004). The chemical structure of specific H4R-antagonists and -agonists are shown in Fig. 4.8.
2.4.2 Structural Biology of Receptor
The human H4-receptor gene was mapped to chromosome 18q11.2 which encodes a 390 amino acid and related to G-protein coupled receptor (GPCR). It shares 37–43% homology (58% in transmembrane regions) with the H3-receptor and is similar in genomic structure (Shahid et al. 2009). The H4R gene spans more than 21 kbp and contains three exons, separated by two large introns (>7 kb) (Table 4.1) with large interspecies variations from 65 to 72% homology in sequences. Analysis of the 5′ flanking region did not reveal the canonical TATA or CAAT-boxes. The promoter region contains several putative regulatory elements involved in proinflammatory cytokine signaling pathways. H4Rs are coupled to Gi/o, which initiates various transduction pathways such as inhibition of forskolin-induced cAMP formation, enhanced calcium influx and MAPK activation. In accordance with the homology between the two receptors, several H3R-agonists and antagonists were recognized by the H4R, although with different affinities. It has been observed that H3R-agonist R-α-methyl histamine acts on H4R with several hundred times less potency. Similar effect has been seen with thioperamide, the classical H3R antagonist which also behaves like a H4R antagonist (Table 4.1), of much lower affinity. Clobenpropit, also a H3R antagonist, exerts agonistic activity on H4R (Shahid et al. 2009).
Histamine binding to H4R is very similar to that reported for the other histamine receptors which show the significance of the Asp94 residue in transmembrane region (TM) 3 and the Glu 182 residue in the TM 5. However, some differences exist and these were exploited to design specific tools. Mouse, rat and guinea pig H4Rs have been cloned and characterized and were found to be only 68, 69, and 65% homologous respectively to their human counterparts. These studies have revealed substantial pharmacological variations between species, with higher affinity of histamine for human and guinea pig receptors than for their rat and mouse equivalents (Liu et al. 2001a, b, Shahid et al. 2009).
2.4.3 Signaling Mechanisms
The signal mechanisms used by the H4R are related to the G-protein-coupled receptors (Gi/o), and its activation leads to an inhibition of adenylyl cyclase and downstream of cAMP responsive elements (CRE) as well as activation of mitogen-activated protein kinase (MAPK) and phospholipase C with Ca2+ mobilization (Table 4.2); see Fig. 4.3 (Shahid et al. 2009).
3 Histamine: Non-Classical Binding Sites
3.1 Cytochrome P450
The human cytochrome P450 (CYP450) superfamily comprises 57 genes encoding heme-containing enzymes, which are found in the liver as well as in extrahepatic tissues (adrenals, and peripheral blood leukocytes), where they can be stimulated by various stimuli (Mahnke et al. 1996, Morgan 2001), see Fig. 4.9. They are not only involved in metabolism of large number of foreign substances, but also play an important role in diverse physiological processes [generation, transformation or inactivation of endogenous ligands (steroids and lipids)], which are involved in cell regulation (Nebert and Russell 2002).
Binding of histamine to CYP450 had been shown by Branders, who proposed a second messenger role for intracellular histamine via this binding site. This hypothesis is mainly based on a finding that N, N diethyl-2-(4-(phenylmethyl)phenoxy) ethanamine (DPPE), an arylalkylamine analogue of tamoxifen inhibits the binding of histamine to CYP450 (Brandes et al. 2002). DPPE allosterically modifies histamine binding to the heme moiety of CYP450 enzymes and inhibits platelet aggregation, as well as lymphocyte and hematopoietic progenitor proliferation (Labella and Brandes 2000). The effect of DPPE on histamine binding was found to be highly complicated and depends on the nature of the P450 enzymes. Thus, it inhibits the action of histamine on CYP2D6 and CYP1A1, enhances its effect on CYP3A4 and does not affect CYP2B6 (Brandes et al. 2000). The heme moiety of CYP450 binds to several histamine antagonists (Hamelin et al. 1998, Kishimoto et al. 1997), particularly H3R antagonists (thioperamide, clobenproprit and ciproxyfan) (Kishimoto et al. 1997). This property explains some effects of these antagonists, when used at high doses. Notably, histamine interacts with CYP450 and it has been demonstrated that CYP2E1 and CYP3A were upregulated in histidine decarboxylase (HDC)-deficient mice (Tamasi et al. 2003).
3.2 Transporters of Histamine
Histamine (2-(1H-imidazol-4-yl) ethanamine) is synthesized in the cytosol and requires a specific transport into secretory vesicles where it is sequestered. Vesicular monoamine transporters (VMATs) are proteins, which accomplish this specific task for several neurotransmitters (Erickson and Varoqui 2000), see Fig. 4.9. The two subtypes of monoamine transporters are VMAT1 and VMAT2 both of which have been cloned and characterized. VMAT2 transports histamine. Vesicular monoamine transporter 2 (VMAT2) had been cloned from rat and human brain, bovine adrenal medulla and a basophilic leukemia cell line (Shahid et al. 2009).
The increased VMAT2 expression in IL-3-dependent cell lines was seen with enhanced histamine synthesis in response to calcium (Ca2+)ionophore (Watson et al. 1999). VMAT2 is responsible for the transport of histamine into secretory granules of enterochromaffin-like (ECL) cells. The gene expression of VMAT2 was found to be modulated by cytokines, either positively (TGFα) or negatively (IL-1 and TNF-α) (Kazumori et al. 2004). VMAT2-deleted granules do not release histamine upon activation, even though granule cell fusion does still occur (Travis et al. 2000). The bone marrow-derived mast cells from histidine decarboxylase (HDC)-deleted mice are completely devoid of endogenous histamine but can take up the mediator from histamine-supplemented medium and store it in secretory granules (Shahid et al. 2009). Hence, two transporters are essential to: (i) insure the passage across the plasma membrane, and (ii) cross the vesicular membrane (Shahid et al. 2009). First transporter has not been identified yet, but the second transporter seems to be vesicular monoamine transporter 2 (VMAT2). The non-neuronal monoamine transporters that actively remove monoamines from extracellular space have been described as organic cation transporter 1 (OCT1), OCT2, and extraneuronal monoamine transporter (EMT). EMT was also designated as OCT3. The expression of OCT1 was found to be restricted to liver, kidney and intestine, OCT2 to brain and kidney, while EMT showed a broad tissue distribution. It has been established that OCT1 cannot transport histamine, compared to OCT2 and EMT for which it is a good substrate (Gründemann et al. 1999). Thus, EMT appeared to be a good candidate as histamine transporter in mast cells and basophils, accounting for their capacity to take up the mediator from the environment (Shahid et al. 2009).
4 Concluding Remarks
Histamine receptors have been important drug targets for many years. Their physiological and pathological relevance and distribution in various tissues are being documented. The exact role of histamine receptors in immunomodulation is still unclear. The scope of histamine research includes immune responses of both the Th1 and Th2 lymphocytes. The newly discovered H4-receptor plays an important role in inflammation and has opened potential way for the function of histamine in inflammation, allergy and autoimmune diseases. Using known receptor agonists and antagonists, many researchers including some of the authors are involved in understanding and enhancing the therapeutic options involving histamine molecule that has been studied for over 100 years.
Abbreviations
- H1R:
-
histamine H1 receptor
- H2R:
-
histamine H2 receptor
- H3R:
-
histamine H3 receptor
- H4R:
-
histamine H4 receptor
- GPCR:
-
G protein-coupled receptor
- mRNA:
-
messenger RNA
- cAMP:
-
cyclic adenosine monophosphate
- Bphs:
-
Bordetella pertussis-induced histamine sensitization
- VAASH:
-
vasoactive amine sensitization elicited by histamine
- Hrh1:
-
histamine H1 receptor gene
- SDS-PAGE:
-
sodium dodecyl sulfate polyacrylamide gel electrophoresis
- CNS:
-
central nervous system
- DAC:
-
1, 2-diacylglycerol
- NO:
-
nitric oxide
- cGMP:
-
cyclic guanosine monophosphate
- NFκB:
-
nuclear factor kappa B
- CHO:
-
chinese hamster ovary
- cDNA:
-
complementary deoxyribonucleic acid
- PKC:
-
protein kinase C
- TM:
-
transmembrane
- cAMP:
-
cyclic adenosine monophosphate
- MAPK:
-
mitogen-activated protein kinase
- IFN:
-
Interferon
- TNF:
-
tumour necrosis factor
- IL:
-
interleukin
- T-cells:
-
T lymphocytes
- MAPK:
-
mitogen-activated protein kinase
- CRE:
-
cAMP responsive elements
- CYP450:
-
cytochrome P450
- DPPE:
-
N, N diethyl-2-(4-(phenylmethyl)phenoxy) ethanamine
- HDC:
-
histidine decarboxylase
- VMATs:
-
vesicular monoamine transporters
- TGF:
-
transforming growth factor
- OCT:
-
organic cation transporter
- EMT:
-
extraneuronal monoamine transporter
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Acknowledgments
Trivendra Tripathi acknowledges University Grants Commission, New Delhi, India for providing UGC Fellowship [UGC letter DON F. 19-33/2006 (CU)] and M. Shahid is grateful to Department of Science & Technology, Ministry of Science and Technology, Government of India for awarding “Young Scientist Project Award” (FT/SR-L-111/2006).
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Shahid, M. et al. (2010). Biological and Pharmacological Aspects of Histamine Receptors and Their Ligands. In: Khardori, N., Khan, R., Tripathi, T. (eds) Biomedical Aspects of Histamine. Springer, Dordrecht. https://doi.org/10.1007/978-90-481-9349-3_4
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