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Vol. 60, Issue 5, 1049-1056, November 2001
School of Sciences (C.S.) and Radioisotopes Laboratory, School of
Pharmacy and Biochemistry (N.F., B.L.L., F.M., C.D.), University of
Buenos Aires, Buenos Aires, Argentina; Institute of Biology and
Experimental Medicine, Buenos Aires, Argentina (C.S., N.F., A.M.,
A.B.); and National Research Council of Argentina, Buenos Aires,
Argentina (F.M., A.B., C.D.)
The histamine H2 receptor (H2r) belongs to the heptahelical receptor
family; upon agonist binding, members of this family activate a G
protein and the downstream effector adenylyl cyclase. Like other G
protein-coupled receptors, exposure of H2r to agonists produces a
desensitization of the response. The present study focused on the
desensitization mechanism of this receptor. Using transiently
transfected COS-7 cells expressing tagged-H2r, the desensitization
induced by amthamine, characterized by decreased cAMP production, was
studied. Results show that the receptor was rapidly desensitized with a
t1/2 = 0.49 ± 0.01 min. Because
of the rapid nature of H2r desensitization, receptor phosphorylation was examined as a likely mechanism for signal attenuation. H2r desensitization was not affected by protein kinases A and C (PKA and
PKC) inhibitors but was remarkably reduced by Zn2+, an
inhibitor of G protein-coupled receptor kinases (GRKs). Cotransfection experiments using tagged H2r and different GRKs (2, 3, 5, or 6), demonstrated that GRK2 and GRK3 were the most potent in augmenting desensitization, causing a reduction in the maximal response to amthamine and a decrease of the t1/2 for
desensitization, whereas GRK5 and GRK6 did not affect the signaling.
Receptor phosphorylation correlates with desensitization for each GRK
studied, whereas phosphorylation that is dependent on protein kinases A
and C seemed irrelevant in receptor signal termination. These results
indicate that in H2r-transfected COS-7 cells, exposure to an agonist
caused desensitization controlled by H2r phosphorylation via GRK2 and GRK3.
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