Phosphorylation-regulated inhibition of the Gz GTPase-activating protein activity of RGS proteins by synapsin I.
Synapsins are neuronal proteins that bind and cluster synaptic vesicles in the presynaptic space, presumably by anchoring to actin filaments, but specific regulatory functions of the synapsins are unknown. We found that a sub-population of brain synapsin Ia, a splice variant of one of three synapsin isoforms, inhibits the GTPase-activating protein (GAP) activity of several RGS proteins. Inhibition is highly selective for Galphaz, a member of the Gi family that is found in neurons, platelets, adrenal chromaffin cells, and a few other neurosecretory cells. Gz has been indirectly implicated in the regulation of secretion. Synapsin Ia constitutes a major fraction of the total GAP-inhibitory activity in brain, and its inhibitory activity is absent from the brains of synapsin I(-/-)/II(-/-) mice. Inhibition depends on the cationic D/E domain of synapsin. Phosphorylation of synapsin Ia at serine 9 by either cyclic AMP-dependent protein kinase or p21-activated protein kinase (PAK1) attenuates its potency as a GAP inhibitor more than 7-fold. Synapsin can thus act as a phosphorylation-modulated mediator of feedback regulation of Gz signaling by the synaptic machinery.
Tu
Yaping
Y
Department of Pharmacology, University of Texas Southwestern Medical Center, Dallas, Texas 75390-9041, USA.
Nayak
Surendra K
SK
Woodson
Jimmy
J
Ross
Elliott M
EM
D017398:Alternative Splicing; D000818:Animals; D001921:Brain / Q000378:metabolism; D002417:Cattle; D002460:Cell Line; D002540:Cerebral Cortex / Q000378:metabolism; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004591:Electrophoresis, Polyacrylamide Gel; D004789:Enzyme Activation; D020558:GTP Phosphohydrolases / Q000378:metabolism*; D020962:Heterotrimeric GTP-Binding Proteins / Q000737:chemistry / Q000502:physiology*; D015151:Immunoblotting; D007313:Insecta; D007700:Kinetics; D010766:Phosphorylation; D020033:Protein Isoforms; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D020710:RGS Proteins / Q000378:metabolism*; D051381:Rats; D012694:Serine / Q000737:chemistry; D015398:Signal Transduction; D016704:Synapsins / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D054462:p21-Activated Kinases
D020033:Protein Isoforms; D020710:RGS Proteins; D016704:Synapsins; C098799:RGS4 protein; D012694:Serine; D017346:Protein Serine-Threonine Kinases; D054462:p21-Activated Kinases; D017868:Cyclic AMP-Dependent Protein Kinases; D020558:GTP Phosphohydrolases; D020962:Heterotrimeric GTP-Binding Proteins