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Calcineurin-mediated protein dephosphorylation in brain nerve terminals regulates the release of glutamate
Journal article   Open access   Peer reviewed

Calcineurin-mediated protein dephosphorylation in brain nerve terminals regulates the release of glutamate

R A Nichols, G R Suplick and J M Brown
The Journal of biological chemistry, v 269(38), pp 23817-23823
23 Sep 1994
DOI: https://doi.org/10.1016/S0021-9258(17)31588-0
PMID: 7522234
Featured in Collection :   UN Sustainable Development Goals @ Drexel
url
https://doi.org/10.1016/s0021-9258(17)31588-0View
Published, Version of Record (VoR)CC BY V4.0,  Open
url
https://doi.org/10.1016/S0021-9258(17)31588-0View
Published, Version of Record (VoR) Open

Abstract

4-Aminopyridine - pharmacology Amino Acid Sequence Animals Calcineurin Calcium - metabolism Calmodulin-Binding Proteins - pharmacology Cell-Free System Cerebral Cortex - metabolism Cyclosporine - pharmacology Dynamins Ethers, Cyclic - pharmacology Glutamates - metabolism GTP Phosphohydrolases - metabolism Membrane Potentials Molecular Sequence Data Nerve Endings - metabolism Nerve Tissue Proteins - metabolism Okadaic Acid Phosphoprotein Phosphatases - metabolism Phosphoprotein Phosphatases - pharmacology Phosphoproteins - metabolism Potassium - pharmacology Potassium Channels - drug effects Rats Synaptic Transmission - drug effects Synaptosomes - metabolism Tacrolimus - analogs & derivatives Tacrolimus - antagonists & inhibitors
In response to Ca2+ entry, several prominent brain nerve terminal phosphoproteins undergo dephosphorylation, but the relation between dephosphorylation and neurotransmitter release is unknown. Using the immunosuppressants cyclosporin A (CsA) and L-683,590 (FK-520) to inhibit specifically the Ca2+/calmodulin-dependent protein phosphatase calcineurin, we demonstrate here that Ca(2+)-dependent dephosphorylation in isolated rat brain nerve terminals (synaptosomes) is mediated by calcineurin. Pretreatment with micromolar CsA resulted in a 76-95% inhibition of stimulation-induced decreases in 32P-labeled dynamin (previously referred to as dephosphin), a phosphoprotein of M(r) = 145,000 (145-kDa protein), and a phosphoprotein of M(r) = 170,000 (170-kDa protein). Pretreatment with FK-520 also inhibited Ca(2+)-dependent dephosphorylation. Using hypotonic lysates of 32P-labeled synaptosomes, the addition of Ca2+ plus calmodulin, but not either agent alone, induced dynamin dephosphorylation. CsA and FK-520 had little to no effect on the release of glutamate induced by either K(+)-depolarization or the Ca2+ ionophore ionomycin. In contrast, calcineurin inhibition led to a substantial enhancement of glutamate release evoked by the K(+)-channel blocker 4-aminopyridine, an agent whose action most closely mimics physiological stimulation. Calcineurin inhibition had no effect on stimulation-induced changes in synaptosomal Ca2+ levels. Based on our findings, we hypothesize that Ca(2+)-dependent protein dephosphorylation resulting from calcineurin activation during physiological stimulation limits neurotransmitter release from brain nerve terminals, perhaps being dependent upon cyclic repolarization of the membrane during stimulation.

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Web of Science research areas
Biochemistry & Molecular Biology
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