PT  - JOURNAL ARTICLE
AU  - Shayo, Carina
AU  - Fernandez, Natalia
AU  - Legnazzi, Bibiana Lemos
AU  - Monczor, Federico
AU  - Mladovan, Alejandro
AU  - Baldi, Alberto
AU  - Davio, Carlos
TI  - Histamine H2 Receptor Desensitization: Involvement of a Select Array of G Protein-Coupled Receptor Kinases
AID  - 10.1124/mol.60.5.1049
DP  - 2001 Nov 01
TA  - Molecular Pharmacology
PG  - 1049--1056
VI  - 60
IP  - 5
4099  - http://molpharm.aspetjournals.org/content/60/5/1049.short
4100  - http://molpharm.aspetjournals.org/content/60/5/1049.full
SO  - Mol Pharmacol2001 Nov 01; 60
AB  - 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 at 1/2 = 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 t 1/2 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.