Pharmacological Characterization of Human Histamine Receptors and Histamine Receptor Mutants in the Sf9 Cell Expression System

  • Erich H. Schneider
  • Roland Seifert
Part of the Handbook of Experimental Pharmacology book series (HEP, volume 241)


A large problem of histamine receptor research is data heterogeneity. Various experimental approaches, the complex signaling pathways of mammalian cells, and the use of different species orthologues render it difficult to compare and interpret the published results. Thus, the four human histamine receptor subtypes were analyzed side-by-side in the Sf9 insect cell expression system, using radioligand binding assays as well as functional readouts proximal to the receptor activation event (steady-state GTPase assays and [35S]GTPγS assays). The human H1R was co-expressed with the regulators of G protein signaling RGS4 or GAIP, which unmasked a productive interaction between hH1R and insect cell Gαq. By contrast, functional expression of the hH2R required the generation of an hH2R-Gsα fusion protein to ensure close proximity of G protein and receptor. Fusion of hH2R to the long (GsαL) or short (GsαS) splice variant of Gαs resulted in comparable constitutive hH2R activity, although both G protein variants show different GDP affinities. Medicinal chemistry studies revealed profound species differences between hH1R/hH2R and their guinea pig orthologues gpH1R/gpH2R. The causes for these differences were analyzed by molecular modeling in combination with mutational studies. Co-expression of the hH3R with Gαi1, Gαi2, Gαi3, and Gαi/o in Sf9 cells revealed high constitutive activity and comparable interaction efficiency with all G protein isoforms. A comparison of various cations (Li+, Na+, K+) and anions (Cl, Br, I) revealed that anions with large radii most efficiently stabilize the inactive hH3R state. Potential sodium binding sites in the hH3R protein were analyzed by expressing specific hH3R mutants in Sf9 cells. In contrast to the hH3R, the hH4R preferentially couples to co-expressed Gαi2 in Sf9 cells. Its high constitutive activity is resistant to NaCl or GTPγS. The hH4R shows structural instability and adopts a G protein-independent high-affinity state. A detailed characterization of affinity and activity of a series of hH4R antagonists/inverse agonists allowed first conclusions about structure/activity relationships for inverse agonists at hH4R. In summary, the Sf9 cell system permitted a successful side-by-side comparison of all four human histamine receptor subtypes. This chapter summarizes the results of pharmacological as well as medicinal chemistry/molecular modeling approaches and demonstrates that these data are not only important for a deeper understanding of HxR pharmacology, but also have significant implications for the molecular pharmacology of GPCRs in general.


[35S]GTPγS binding GPCRs Histamine receptors Radioligand binding Sf9 insect cells Steady-state GTPase assay 



Tritiated histamine


Tritiated N α-methylhistamine


GTPγS, labeled with 35S


α-Adrenoceptor, subtype 2

β1AR, β2AR

β-Adrenoceptor subtypes


β2-Adrenoceptor, constitutively active mutant


GTP, γ-labeled with 32P


Adenosine receptor subtype 2A


Adenylyl cyclase


Atypical chemokine receptor 1


N G-acylated imidazolylpropylguanidines


Bradykinin B2 receptor

Balb/C, C57Bl/6

Mouse strains


3′,5′-Cyclic adenosine monophosphate


C–C chemokine receptor type 5


Central nervous system

D1R, D2R

Dopamine receptor subtypes


Aspartate–arginine–tyrosine motif at the bottom of the third transmembrane helix of a GPCR


Extracellular loop (e.g. e2)


Experimental autoimmune encephalitis


Extracellular loop


Peptide tag (DYKDDDDK)


Formyl peptide receptor 1


FPR1 isoform


Receptor for γ-amino butyric acid, subtype B


Gα-interacting protein (= regulator of G protein signaling RGS19)




Guinea pig (prefix)


G protein-coupled receptor


Stimulatory G protein, long splice variant


Stimulatory G protein, short splice variant




Guanosine 5′-O-[γ-thio]triphosphate (non-hydrolysable GTP derivative)

i1, Gαi2, Gαi3, Gαi/o

Inhibitory G protein isoforms


G protein isoform activating phospholipase C


Stimulatory G protein


G protein complex, consisting of Gβ1 and Gγ2


Human (prefix)


Chimeric receptor (human H1R with second extracellular loop from guinea pig H1R)


Chimeric receptor (human H1R with N-terminus and second extracellular loop from guinea pig H1R)

H1R, H2R, H3R, H4R

Histamine receptor subtypes


Histidine decarboxylase


Cervix carcinoma cell line


Hexahistidine tag


Human promyelocytic leukemia cell line


High performance liquid chromatography-coupled tandem mass spectrometry


Ligand dissociation constant


Michaelis–Menten constant, substrate concentration resulting in 50% of maximum enzymatic reaction speed

LH/CG receptor

Receptor for luteinizing hormone/choriogonadotropin


Murine (prefix)


Muscarinic receptor subtype 3


N α-methylhistamine


Fusion protein of GsαS with a chimeric receptor (N-terminus to transmembrane domain 3 from guinea pig H2R plus transmembrane domain 4 to C-terminus from human H2R)


Fusion protein of GsαS with a chimeric receptor (N-terminus to transmembrane domain 3 from human H2R plus transmembrane domain 4 to C-terminus from guinea pig H2R)


Negative decadic logarithm of the agonist concentration that causes 50% of the maximum effect


Negative decadic logarithm of the antagonist concentration that causes 50% inhibition


Negative decadic logarithm of a dissociation constant determined in a functional assay


Protein kinase C


Negative decadic logarithm of a dissociation constant determined in a competition binding assay


Phospholipase C


Pertussis toxin


Rat (prefix)




Regulator of G protein signaling 4


Structure-activity relationship


Murine lymphoma cell line

Sf9, Sf21

Insect cell lines originating from ovarian cells of Spodoptera frugiperda

Th1, Th2

Differentially polarized T helper cell subgroups


Transmembrane helix of a G protein-coupled receptor


Tuberomamillary nucleus

U373 MG

Human astrocytoma cell line


Maximum enzymatic reaction speed in the presence of saturating substrate concentrations


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© Springer International Publishing AG 2017

Authors and Affiliations

  1. 1.Institute of Pharmacology, Medical School of HannoverHannoverGermany

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