Gq pathway desensitizes chemotactic receptor-induced calcium signaling via inositol trisphosphate receptor down-regulation

Abstract

Desensitization of a chemotactic receptor is an adaptive process that terminates inflammation. Although homologous desensitization can be well explained by the action of specific receptor kinases, the mechanisms of heterologous desensitization remain elusive. As an approach to evaluate the roles of Gq pathway in desensitization of calcium signaling, we expressed a constitutively active Gqα mutant (Gqα Q-L) together with platelet-activating factor (PAF) receptor in Xenopus laevis oocytes. Gqα Q-L expression completely attenuated the calcium-sensitive chloride current and the 45Ca release elicited by PAF. The Gq-mediated desensitization could not be ascribed to G protein/receptor uncoupling via receptor phosphorylation, because (i) PAF-induced inositol 1,4,5-trisphosphate (IP3) synthesis was only partially suppressed and (ii) a mutated PAF receptor devoid of all Ser and Thr in the third cytoplasmic loop and in the C-terminal tail was also completely desensitized by GqαQ-L. In Gqα Q-L expressing oocytes, microinjection of IP3 failed to elicit the calcium response, and the IP3 receptor, detected by a specific antibody, disappeared. Thus, the Gq-mediated desensitization can be most likely explained by IP3 receptor down-regulation. These novel mechanisms may explain in part heterologous desensitization in chemotactic factor-stimulated inflammatory cells.