Selective Receptor Desensitization

Science's STKE  30 May 2000:
Vol. 2000, Issue 34, pp. tw6
DOI: 10.1126/stke.2000.34.tw6

Like many other G protein-coupled receptors that induce diverse cellular responses, the metabotropic glutamate receptor α (mGluR1α) can simultaneously activate multiple signaling cascades in neuronal and glial cells where the receptors are expressed. This is based on the receptor's ability to couple to the Gq/11 subunit, thereby activating the IP3/Ca2+ pathway, and to the Gs subunit, which stimulates the cAMP pathway. Francesconi and Duvoisin show that desensitization of the IP3/Ca2+ pathway is a selective process mediated by protein kinase C (PKC). In contrast, PKC had no effect on receptor signaling through cAMP. However, activation of protein kinase A (PKA) enhanced IP3 signaling, even in the absence of agonist. The selectivity of PKC's effects arises from the phosphorylation of a threonine residue on the receptor that disrupts Gq/11 interaction with mGluR1α without altering signaling through Gs. Hence, activation of PKC consequent to signaling through IP3 induces feedback inhibition that is specific only to this activation pathway.

Francesconi, A., and Duvoisin, R.M. (2000) Opposing effects of protein kinase C and protein kinase A on metabotropic glutamate receptor signaling: Selective desensitization of the inositol trisphosphate/Ca2+ pathway by phosphorylation of the receptor-G protein-coupling domain. Proc. Natl. Acad. Sci. U.S.A. 97: 6185-6190. [Abstract] [Full Text]