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

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

Abstract

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.

Keywords

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

Abbreviations

[3H]histamine

Tritiated histamine

[3H]NAMH

Tritiated N α-methylhistamine

[35S]GTPγS

GTPγS, labeled with 35S

α2AR

α-Adrenoceptor, subtype 2

β1AR, β2AR

β-Adrenoceptor subtypes

β2ARCAM

β2-Adrenoceptor, constitutively active mutant

[γ-32P]GTP

GTP, γ-labeled with 32P

A2aR

Adenosine receptor subtype 2A

AC

Adenylyl cyclase

ACKR1

Atypical chemokine receptor 1

AIPGs

N G-acylated imidazolylpropylguanidines

B2R

Bradykinin B2 receptor

Balb/C, C57Bl/6

Mouse strains

cAMP

3′,5′-Cyclic adenosine monophosphate

CCR5

C–C chemokine receptor type 5

CNS

Central nervous system

D1R, D2R

Dopamine receptor subtypes

DRY

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

e

Extracellular loop (e.g. e2)

EAE

Experimental autoimmune encephalitis

ECL

Extracellular loop

FLAG

Peptide tag (DYKDDDDK)

FPR1

Formyl peptide receptor 1

FPR26

FPR1 isoform

GABABR

Receptor for γ-amino butyric acid, subtype B

GAIP

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

GDP

Guanosine-5′-diphosphate

gp

Guinea pig (prefix)

GPCR

G protein-coupled receptor

GsαL

Stimulatory G protein, long splice variant

GsαS

Stimulatory G protein, short splice variant

GTP

Guanosine-5′-triphosphate

GTPγS

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

i1, Gαi2, Gαi3, Gαi/o

Inhibitory G protein isoforms

q

G protein isoform activating phospholipase C

s

Stimulatory G protein

1γ2

G protein complex, consisting of Gβ1 and Gγ2

h

Human (prefix)

h(gpE2)H1R

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

h(gpNgpE2)H1R

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

H1R, H2R, H3R, H4R

Histamine receptor subtypes

HDC

Histidine decarboxylase

HeLa

Cervix carcinoma cell line

His6

Hexahistidine tag

HL-60

Human promyelocytic leukemia cell line

HPLC-MS/MS

High performance liquid chromatography-coupled tandem mass spectrometry

KD

Ligand dissociation constant

KM

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

LH/CG receptor

Receptor for luteinizing hormone/choriogonadotropin

m

Murine (prefix)

M3R

Muscarinic receptor subtype 3

NAMH

N α-methylhistamine

NgpChH2R-GsαS

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)

NhCgpH2R-GsαS

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)

pEC50

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

pIC50

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

pKb

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

PKC

Protein kinase C

pKi

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

PLC

Phospholipase C

PTX

Pertussis toxin

r

Rat (prefix)

RAMH

(R)-α-methylhistamine

RGS4

Regulator of G protein signaling 4

SAR

Structure-activity relationship

S49

Murine lymphoma cell line

Sf9, Sf21

Insect cell lines originating from ovarian cells of Spodoptera frugiperda

Th1, Th2

Differentially polarized T helper cell subgroups

TM

Transmembrane helix of a G protein-coupled receptor

TMN

Tuberomamillary nucleus

U373 MG

Human astrocytoma cell line

Vmax

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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