Multiple differences in agonist and antagonist pharmacology between human and guinea pig histamine H1-receptor

Species isoforms of histamine H-2-, H-3-, and H-4-receptors differ in their pharmacological properties. The study aim was to dissect differences between the human H1R (hH(1)R) and guinea pig H1R (ghH(1)R). We coexpressed hH(1)R and gpH(1)R with regulators of G-protein signaling in Sf9 insect cells and analyzed the GTPase activity of G(q)-proteins. Small H1R agonists showed similar effects at hH(1)R and gpH(1)R, whereas bulkier 2-phenylhistamines and histaprodifens were up to similar to10-fold more potent at gpH(1)R than at hH(1)R. Most 2-phenylhistamines and histaprodifens were more efficacious at gpH(1)R than at hH(1)R. Several first-generation H1R antagonists were similar to2-fold, and arpromidine-type H1R antagonists up to similar to10-fold more potent at gpH(1)R than at hH(1)R. [H-3] Mepyramine competition binding studies confirmed the potency differences of the GTPase studies. Phe-153-->Leu-153 or Ile-433-->Val-433 exchange in hH(1)R (hH(1)R-->gpH(1)R) resulted in poor receptor expression, low [H-3] mepyramine affinity, and functional inactivity. The Phe-153-->Leu-153/Ile-433-->Val-433 double mutant expressed excellently but only partially changed the pharmacological properties of hH(1)R. Small H1R agonists and 2-phenylhistamines interacted differentially with human and guinea pig H 2 R in terms of potency and efficacy, respectively. Our data show the following: 1) there are differences in agonist- and antagonist-pharmacology of hH(1)R and gpH(1)R encompassing diverse classes of bulky ligands. These differences may be explained by higher conformational flexibility of gpH(1)R relative to hH(1)R; 2) Phe-153 and Ile-433 are critical for proper folding and expression of hH(1)R; and 3) H2R species isoforms distinguish between H1R agonists.