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Vol. 60, Issue 6, 1210-1225, December 2001
Departments of Pharmacology and Toxicology (M.T.K., K.W.-S., R.S.)
and Molecular Biosciences (T.B.), the University of Kansas, Lawrence,
Kansas; and Department of Pharmacy, University of Regensburg,
Regensburg, Germany (S.D., A.B.)
It is unknown why the potencies and efficacies of long-chained
guanidine-type histamine H2-receptor (H2R)
agonists are lower at the H2R of human neutrophils than at
the H2R of the guinea pig atrium. To elucidate these
differences, we analyzed fusion proteins of the human H2R
(hH2R) and guinea pig H2R (gpH2R),
respectively, and the short splice variant of Gs
(GsS) expressed in Sf9 cells. The potencies and
efficacies of small H2R agonists in the GTPase assay and
the potencies of antagonists at inhibiting histamine-stimulated GTP
hydrolysis by hH2R-GsS and
gpH2R-GsS were similar. In contrast, the
potencies and efficacies of guanidines were lower at
hH2R-GsS than at
gpH2R-GsS. Guanidines bound to
hH2R-GsS with lower affinity than to
gpH2R-GsS, and high-affinity binding of
guanidines at gpH2R-GsS was more resistant
to disruption by GTP
S than binding at
hH2R-GsS. Molecular modeling suggested that
the nonconserved Asp-271 in transmembrane domain 7 of gpH2R
(Ala-271 in hH2R) confers high potency to guanidines. This
hypothesis was confirmed by Ala-271
Asp-271 mutation in
hH2R-GsS. Intriguingly, the efficacies of
guanidines at the Ala-271Asp-271 mutant and at
hH2R/gpH2R chimeras were lower than at
gpH2R. Our model suggests that a Tyr-17/Asp-271 H-bond,
present only in gpH2R-GsS but not the other
constructs studied, stabilizes the active guanidine-H2R
state. Collectively, our data show 1) distinct interaction of
H2R species isoforms with guanidines, 2) that a single
amino acid in transmembrane domain 7 critically determines guanidine
potency, and 3) that an interaction between transmembrane domains 1 and
7 is important for guanidine efficacy.
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