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Glutamate Exocytosis and MARCKS Phosphorylation Are Enhanced by a Metabotropic Glutamate Receptor Coupled to a Protein Kinase C Synergistically Activated by Diacylglycerol and Arachidonic Acid

Abstract: 4‐Aminopyridine evokes repetitive firing of synaptosomes and exocytosis of glutamate by inhibiting a dendrotoxin‐sensitive K+ channel responsible for stabilizing the membrane potential. We have shown previously that activation of protein kinase C (PKC) by high concentrations of phorbol ester (4β‐phorbol dibutyrate) can increase release by inhibiting a dendrotoxin‐insensitive ion channel, whereas the metabotropic glutamate receptor (mGluR) agonist (1S,3R)‐1‐aminocyclopentane‐1,3‐dicarboxylate [(1S,3R)‐ACPD] mimics the action of 4β‐phorbol dibutyrate, but only in the presence of 2 µM arachidonic acid (AA). In this article, we investigate the role of AA. AA plus (1S,3R)‐ACPD is without effect on KCl‐induced glutamate exocytosis, indicating that the regulatory pathway acts upstream of the release‐coupled Ca2+ channel or Ca2+‐secretion coupling. Diacylglycerol concentrations are greatly enhanced by (1S,3R)‐ACPD alone, independently of AA, indicating that AA acts downstream of phospholipase C. Myristoylated alanine‐rich C kinase substrate (MARCKS) is the major presynaptic substrate for PKC. mGluR activation by (1S,3R)‐ACPD enhances phosphorylation of MARCKS, but only in the presence of AA. These results strongly suggest that AA acts on presynaptic PKC synergistically with diacylglycerol generated by the phospholipase‐coupled mGluR, consistent with the known behaviour of certain purified PKC isoforms. The magnitude of the effects observed in a population of rat cerebrocortical synaptosomes suggests that this is a major mechanism regulating the release of the brain's dominant excitatory neurotransmitter and supports the concept that AA, or a related compound with a similar locus of action, may in certain circumstances play a role in synaptic plasticity.