Distinct pharmacology of rat and human histamine H(3) receptors: role of two amino acids in the third transmembrane domain.
Starting from the sequence of the human histamine H(3) receptor (hH(3)R) cDNA, we have cloned the corresponding rat cDNA. Whereas the two deduced proteins show 93.5% overall homology and differ only by five amino acid residues at the level of the transmembrane domains (TMs), some ligands displayed distinct affinities. Thioperamide and ciproxifan were about 10 fold more potent at the rat than at the human receptor, whereas FUB 349 displayed a reverse preference. Histamine, (R)alpha-methylhistamine, proxyfan or clobenpropit were nearly equipotent at H(3) receptors of both species. The inverse discrimination patterns of ciproxifan and FUB 349 were partially changed by mutation of one amino acid (V122A), and fully abolished by mutation of two amino acids (A119T and V122A), in TM3 of the rH(3)R located in the vicinity of Asp(114) purported to salt-link the ammonium group of histamine. Therefore, these two residues appear to be responsible for the distinct pharmacology of the H(3)R in the two species.
Ligneau
X
X
Unité de Neurobiologie et Pharmacologie Moléculaire (U.109) de l'INSERM, Centre Paul Broca, 2ter rue d'Alésia, 75014 Paris, France.
Morisset
S
S
Tardivel-Lacombe
J
J
Gbahou
F
F
Ganellin
C R
CR
Stark
H
H
Schunack
W
W
Schwartz
J C
JC
Arrang
J M
JM
D000595:Amino Acid Sequence; D019943:Amino Acid Substitution; D000596:Amino Acids / Q000235:genetics / Q000502:physiology; D000818:Animals; D001667:Binding, Competitive / Q000187:drug effects; D019556:COS Cells; D018076:DNA, Complementary / Q000235:genetics; D004305:Dose-Response Relationship, Drug; D006633:Histamine Antagonists / Q000494:pharmacology; D006801:Humans; D007093:Imidazoles / Q000378:metabolism / Q000494:pharmacology; D008565:Membrane Proteins / Q000737:chemistry / Q000235:genetics; D008969:Molecular Sequence Data; D016297:Mutagenesis, Site-Directed; D009154:Mutation; D010880:Piperidines / Q000494:pharmacology; D017434:Protein Structure, Tertiary; D011869:Radioligand Assay; D051381:Rats; D018100:Receptors, Histamine H3 / Q000187:drug effects / Q000235:genetics* / Q000378:metabolism; D016415:Sequence Alignment; D017386:Sequence Homology, Amino Acid; D014316:Tritium
D000596:Amino Acids; D018076:DNA, Complementary; D006633:Histamine Antagonists; D007093:Imidazoles; D008565:Membrane Proteins; D010880:Piperidines; D018100:Receptors, Histamine H3; D014316:Tritium; C090115:iodoproxyfan; C115705:ciproxifan; C052075:thioperamide