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The role of protein kinase C and its neuronal substrates dephosphin, B-50, and MARCKS in neurotransmitter release

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Abstract

This article focuses on the role of protein phosphorylation, especially that mediated by protein kinase C (PKC), in neurotransmitter release. In the first part of the article, the evidence linking PKC activation to neurotransmitter release is evaluated. Neurotransmitter release can be elicited in at least two manners that may involve distinct mechanisms:Evoked release is stimulated by calcium influx following chemical or electrical depolarization, whereasenhanced release is stimulated by direct application of phorbol ester or fatty acid activators of PKC. A markedly distinct sensitivity of the two pathways to PKC inhibitors or to PKC downregulation suggests that onlyenhanced release is directly PKC-mediated. In the second part of the article, a framework is provided for understanding the complex and apparently contrasting effects of PKC inhibitors. A model is proposed whereby the site of interaction of a PKC inhibitor with the enzyme dictates the apparent potency of the inhibitor, since the multiple activators also interact with these distinct sites on the enzyme. Appropriate PKC inhibitors can now be selected on the basis of both the PKC activator used and the site of inhibitor interaction with PKC. In the third part of the article, the known nerve terminal substrates of PKC are examined. Only four have been identified, tyrosine hydroxylase, MARCKS, B-50, and dephosphin, and the latter two may be associated with neurotransmitter release. Phosphorylation of the first three of these proteins by PKC accompanies release. B-50 may be associated withevoked release since antibodies delivered into permeabilized synaptosomes blockevoked, but not enhanced release. Dephosphin and its PKC phosphorylation may also be associated withevoked release, but in a unique manner. Dephosphin is a phosphoprotein concentrated in nerve terminals, which, upon stimulation of release, is rapidly dephosphorylated by a calcium-stimulated phosphatase (possibly calcineurin [CN]). Upon termination of the rise in intracellular calcium, dephosphin is phosphorylated by PKC. A priming model of neurotransmitter release is proposed where PKC-mediated phosphorylation of such a protein is an obligatory step thatprimes the release apparatus, in preparation for a calcium influx signal. Protein dephosphorylation may therefore be as important as protein phosphorylation in neurotransmitter release.

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Abbreviations

AA:

arachidonic acid

CaM:

calmodulin

CaM-PK:

calmodulin-dependent protein kinase

CN:

calcineurin

PKA:

cAMP-dependent protein kinase

PKC:

protein kinase C

PLA2 :

phospholipase A2

PMA:

phorbol 12-myristate 13-acetate

PS:

l-phosphatidyl-l-serine

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Correspondence to Phillip J. Robinson.

Additional information

While this manuscript was under review, another comprehensive review of the role of PKC in neurotransmitter release was published by Gispen's group (Dekker et al., 1991a).

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Robinson, P.J. The role of protein kinase C and its neuronal substrates dephosphin, B-50, and MARCKS in neurotransmitter release. Mol Neurobiol 5, 87–130 (1991). https://doi.org/10.1007/BF02935541

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Index Entries

  • Dephosphin
  • protein kinase C
  • isozymes
  • phorbol esters
  • protein phosphorylation
  • synaptosomes
  • neurotransmitter release
  • protein kinase C inhibitors
  • calcineurin