Protein Phosphatase 1 and 2A Inhibitors Prolong the Switch in the Control of Glutamate Release by Group I Metabotropic Glutamate Receptors

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Abstract
We have addressed the role of protein phosphatases (PPs) in the modulation of the switch in glutamate release observed after repetitive stimulation of group I metabotropic glutamate receptors (mGluRs). In cerebrocortical nerve terminals the agonist (S)‐3,5‐dihydroxyphenylglycine facilitated evoked glutamate release. However, a second stimulation, 5 min later, reduced rather than facilitated this release. This switch in the control of glutamate release was reversed when a 30‐min interval was left between stimulations. Inhibition of the endogenous PPs, PP1 and PP2A, with calyculin A and okadaic acid prevented the recovery of the facilitatory response and maintained the receptor permanently coupled to the inhibitory pathway. The inhibitors of PP2B, cyclosporin A and cypermethrine, had no effect. The inhibition of glutamate release was insensitive to pertussis toxin and was the result of the loss of the release component coupled to N‐type Ca2+ channels. This inhibitory action was suppressed by addition of the protein kinase C activator 4β‐phorbol 12,13‐dibutyrate. We conclude that the balance between protein kinase and phosphatase activity at the nerve terminal plays a key role in accommodating the modulation of glutamate release by group I mGluRs.