期刊
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
卷 97, 期 11, 页码 6185-6190出版社
NATL ACAD SCIENCES
DOI: 10.1073/pnas.97.11.6185
关键词
-
资金
- NEI NIH HHS [R01 EY009534, EY09534] Funding Source: Medline
Signaling by the metabotropic glutamate receptor 1 alpha (mGluR1 alpha) can lead to the accumulation of inositol 1,4,5-trisphosphate (InsP(3)) and cAMP and to the modulation of K+ and Ca2+ channel opening, At present, very little is known about how these different actions are integrated and eventually turned off. Unraveling the molecular mechanisms underlying these functions is crucial for understanding mGluR-mediated regulation of synaptic transmission. It has been shown that receptor-induced activation of the lnsP(3) pathway is subject to feedback inhibition mediated by protein kinase C (PKC), In this study, we provide evidence for a differential regulation by PKC and protein kinase A of two distinct mGluR1 alpha-dependent signaling pathways, PKC activation selectively inhibits agonist-dependent stimulation of the InsP(3) pathway but does not affect receptor signaling via cAMP, In contrast, protein kinase A potentiates agonist-independent signaling of the receptor via lnsP3, furthermore, we demonstrate that the selectivity of PKC action on receptor signaling rests on phosphorylation of a threonine residue located in the G protein-interacting domain of the receptor. Modification at Thr(695) selectively disrupts mGluR1 alpha-G(q/11) interaction without affecting signaling through G(s), Together, these data provide insight on the mechanisms by which selective downregulation of a specific receptor-dependent signaling pathway can be achieved and on how cross-talk between different second messenger cascades may contribute to fine-tune short- and long-term receptor activity.
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