A network of control mediated by regulator of calcium/calmodulin-dependent signaling.
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 Ser55 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.
Rakhilin
S V
SV
Laboratory of Molecular and Cellular Neuroscience, Rockefeller University, New York, NY 10021, USA.
Olson
P A
PA
Nishi
A
A
Starkova
N N
NN
Fienberg
A A
AA
Nairn
A C
AC
Surmeier
D J
DJ
Greengard
P
P
D000818:Animals; D019703:Calcineurin / Q000378:metabolism; D065095:Calcineurin Inhibitors; D002118:Calcium / Q000378:metabolism*; D020746:Calcium Channels, L-Type / Q000378:metabolism; D020013:Calcium Signaling; D002147:Calmodulin / Q000378:metabolism*; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D051937:Dopamine and cAMP-Regulated Phosphoprotein 32; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D017072:Neostriatum / Q000166:cytology / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000378:metabolism; D009474:Neurons / Q000378:metabolism; D010750:Phosphoproteins / Q000378:metabolism*; D010766:Phosphorylation; D043643:Receptor, Muscarinic M1 / Q000378:metabolism; D017447:Receptors, Dopamine D1 / Q000378:metabolism; D015398:Signal Transduction
D065095:Calcineurin Inhibitors; D020746:Calcium Channels, L-Type; D002147:Calmodulin; D051937:Dopamine and cAMP-Regulated Phosphoprotein 32; D009419:Nerve Tissue Proteins; D010750:Phosphoproteins; D043643:Receptor, Muscarinic M1; D017447:Receptors, Dopamine D1; C061368:cyclic AMP-regulated phosphoprotein ARPP-21; D017868:Cyclic AMP-Dependent Protein Kinases; D019703:Calcineurin; D002118:Calcium