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Vol. 55, Issue 1, 92-101, January 1999
Institut National de la Santé et de la Recherche
Médicale U 439, 34090 Montpellier, France (J.M., C.K., T.G.,
R.L., C.L., B.D., J.-C.B.);
Laboratoires Fournier, 21121 Daix, France
(D.P., J.-L.P.); and
Laboratoire de Chimie Théorique,
Université de Nancy I, 54506 Vandoeuvre-les-Nancy
Cédex, France (B.M.)
We report that mutation of specific residues in the human
B2 bradykinin (BK) receptor induces its marked constitutive
activation, evaluated through inositol phosphate production in COS-7
cells expressing the wild-type or mutant receptors. We provide evidence for a strikingly high constitutive activation of the B2
receptor induced by alanine substitution of the Asn113
residue, located in the third transmembrane domain. These results are
reminiscent of our previous finding that mutation of the homologous Asn111 residue induces constitutive activation of the
AT1 angiotensin II receptor. BK overstimulation of the
constitutively activated mutant N113A receptor was also observed. Phe
replacement of the Trp256 residue, fairly conserved in
transmembrane domain VI of G protein-coupled receptors, also induced a
less prominent but significant constitutive activation. Interestingly,
the peptidic HOE 140 compound and an original nonpeptidic compound LF
16 0335, which both behaved as inverse agonists of the wild-type
receptor expressed in COS-7 cells, became potent and efficient agonists
of the two constitutively activated mutant N113A and W256F receptors.
These parallel changes observed for two chemically unrelated series can
serve as a basis for future studies of structure-function relationships
and modeling of activation processes, based on a detailed analysis of
the network of helix-helix interactions, which stabilize the inactive
receptor conformation and undergo rearrangements on transition to
activated states.
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