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The Journal of Neuroscience, October 15, 2001, 21(20):7944-7953

Opposing Changes in Phosphorylation of Specific Sites in Synapsin I During Ca²⁺-Dependent Glutamate Release in Isolated Nerve Terminals

Jasmina N. Jovanovic^{1, 2}, Talvinder S. Sihra², Angus C. Nairn¹, Hugh C. Hemmings Jr³, Paul Greengard¹, and Andrew J. Czernik¹

¹ Laboratory of Molecular and Cellular Neuroscience, The Rockefeller University, New York, New York 10021, ² Department of Pharmacology, University College, London, WC1E 6BT, United Kingdom, and ³ Departments of Anesthesiology and Pharmacology, Weill Medical College of Cornell University, New York, New York 10021

Synapsins are major neuronal phosphoproteins involved in regulation of neurotransmitter release. Synapsins are well established targets for multiple protein kinases within the nerve terminal, yet little is known about dephosphorylation processes involved in regulation of synapsin function. Here, we observed a reciprocal relationship in the phosphorylation-dephosphorylation of the established phosphorylation sites on synapsin I. We demonstrate that, in vitro, phosphorylation sites 1, 2, and 3 of synapsin I (P-site 1 phosphorylated by cAMP-dependent protein kinase; P-sites 2 and 3 phosphorylated by Ca²⁺-calmodulin-dependent protein kinase II) were excellent substrates for protein phosphatase 2A, whereas P-sites 4, 5, and 6 (phosphorylated by mitogen-activated protein kinase) were efficiently dephosphorylated only by Ca²⁺-calmodulin-dependent protein phosphatase 2B-calcineurin. In isolated nerve terminals, rapid changes in synapsin I phosphorylation were observed after Ca²⁺ entry, namely, a Ca²⁺-dependent phosphorylation of P-sites 1, 2, and 3 and a Ca²⁺-dependent dephosphorylation of P-sites 4, 5, and 6. Inhibition of calcineurin activity by cyclosporin A resulted in a complete block of Ca²⁺-dependent dephosphorylation of P-sites 4, 5, and 6 and correlated with a prominent increase in ionomycin-evoked glutamate release. These two opposing, rapid, Ca²⁺-dependent processes may play a crucial role in the modulation of synaptic vesicle trafficking within the presynaptic terminal.

Key words: 4-aminopyridine; brain-derived neurotrophic factor (BDNF); Ca²⁺; calcineurin; cyclosporin A; glutamate; ionomycin; mitogen-activated protein (MAP) kinase; neurotrophins; okadaic acid; PD98059; phosphatases; synapsins; synaptosomes; neurotransmitter release

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Copyright © 2001 Society for Neuroscience  0270-6474/01/21207944-10$05.00/0

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