Journal
SCIENCE
Volume 306, Issue 5696, Pages 698-701Publisher
AMER ASSOC ADVANCEMENT SCIENCE
DOI: 10.1126/science.1099961
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Funding
- NIDA NIH HHS [DA12958, DA10044, P01 DA010044] Funding Source: Medline
- NIMH NIH HHS [MH40899] Funding Source: Medline
- NINDS NIH HHS [NS34696] Funding Source: Medline
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Calmodulin (CaM) is A major effector for the intracellular actions of Ca2+ in nearly all cell types. We identified a CaM-binding protein, designated regulator of calmodulin signaling (RCS). G protein-coupled receptor (GPCR)-dependent activation of protein kinase A (PKA) led to phosphorylation of RCS at Ser(55) and increased its binding to CaM. Phospho RCS acted as a competitive inhibitor of CaM-dependent enzymes, including protein phosphatase 2B (PP2B, also called calcineurin). Increasing RCS phosphorylation blocked GPCR- and PP2B-mediated suppression of L-type Ca2+ currents in striatal neurons. Conversely, genetic deletion of RCS significantly increased this modulation. Through a molecular mechanism that amplifies GPCR- and PKA-mediated signaling and attenuates GPCR- and PP2B-mediated signaling, RCS synergistically increases the phosphorylation of key proteins whose phosphorylation is regulated by PKA and PP2B.
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