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CELLULAR AND MOLECULAR
Department of Pharmacology and Toxicology, the University of Kansas, Lawrence, Kansas (R.S., K.W.-S.); Department of Molecular Biosciences, the University of Kansas, Lawrence, Kansas (T.B.); Department of Chemistry and Biochemistry, Free University of Berlin, Berlin, Germany (T.B.); Institute of Pharmacy, Free University of Berlin, Berlin, Germany (H.H.P., W.S.); Institute of Pharmacy, University of Regensburg, Regensburg, Germany (S.D., A.B., S.E.)
Species isoforms of histamine H2-, H3-, and
H4-receptors differ in their pharmacological properties. The study
aim was to dissect differences between the human H1R
(hH1R) and guinea pig H1R (ghH1R). We
coexpressed hH1R and gpH1R with regulators of G-protein
signaling in Sf9 insect cells and analyzed the GTPase activity of
Gq-proteins. Small H1R agonists showed similar effects
at hH1R and gpH1R, whereas bulkier 2-phenylhistamines
and histaprodifens were up to 
10-fold more potent at gpH1R
than at hH1R. Most 2-phenylhistamines and histaprodifens were more
efficacious at gpH1R than at hH1R. Several
first-generation H1R antagonists were 2-fold, and
arpromidine-type H1R antagonists up to 10-fold more potent at
gpH1R than at hH1R. [3H]Mepyramine
competition binding studies confirmed the potency differences of the GTPase
studies. Phe-153
Leu-153 or Ile-433Val-433 exchange in
hH1R (hH1RgpH1R) resulted in poor
receptor expression, low [3H]mepyramine affinity, and functional
inactivity. The Phe-153Leu-153/Ile-433Val-433 double mutant
expressed excellently but only partially changed the pharmacological
properties of hH1R. Small H1R agonists and
2-phenylhistamines interacted differentially with human and guinea pig
H2R in terms of potency and efficacy, respectively. Our data show
the following: 1) there are differences in agonist- and
antagonist-pharmacology of hH1R and gpH1R encompassing
diverse classes of bulky ligands. These differences may be explained by higher
conformational flexibility of gpH1R relative to hH1R; 2)
Phe-153 and Ile-433 are critical for proper folding and expression of
hH1R; and 3) H2R species isoforms distinguish between
H1R agonists.
Address correspondence to: Dr. Roland Seifert, Department of Pharmacology and Toxicology, The University of Kansas, Malott Hall, Room 5064, 1251 Wescoe Hall Drive, Lawrence, KS 66045-7582. E-mail: rseifert{at}ku.edu
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