Protein phosphatase 2B inhibitors mimic the action of arachidonic acid and prolong the facilitation of glutamate release by group I mGlu receptors.
We have addressed the role of arachidonic acid in the facilitation of glutamate release by group I metabotropic glutamate (mGlu) receptors. The activation of these receptors with the specific agonist 3,5-dihydroxyphenylglycine (DHPG) failed to enhance the cumulative Ca(2+)-dependent release of glutamate evoked by a 5 min depolarization with 4-aminopyridine, in the absence but not in the presence of arachidonic acid. However, DHPG, in the absence of arachidonic acid, transiently enhanced diacylglycerol levels, transiently potentiated 4AP-evoked depolarization, and significantly enhanced the fast but not the slow component of glutamate release observed after prolonged stimulations of nerve terminals. Further evidence that DHPG was able to initiate release facilitation in the absence of arachidonic acid was obtained in experiments where the protein phosphatase 2B (cyclosporine A and cypermethrine) but not protein phosphatase 1 or 2A inhibitors (okadaic acid and calyculin A) facilited glutamate release to a maximal extent comparable to that induced by arachidonic acid. We conclude that an active protein phosphatase 2B (calcineurin) dephosphorylates the presynaptic target/s responsible for facilitation of glutamate release.
Sistiaga
A
A
Departamento de Bioquímica, Facultad de Veterinaria, Universidad Complutense, 28040, Madrid, Spain.
Sánchez-Prieto
J
J
D015761:4-Aminopyridine / Q000494:pharmacology; D000818:Animals; D016718:Arachidonic Acid / Q000494:pharmacology*; D019703:Calcineurin / Q000378:metabolism; D065095:Calcineurin Inhibitors; D002118:Calcium / Q000378:metabolism / Q000494:pharmacology; D016572:Cyclosporine / Q000494:pharmacology; D004075:Diglycerides / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D018698:Glutamic Acid / Q000187:drug effects* / Q000378:metabolism; D005998:Glycine / Q000031:analogs & derivatives / Q000494:pharmacology; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects; D054645:Protein Phosphatase 1; D011722:Pyrethrins / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D018094:Receptors, Metabotropic Glutamate / Q000187:drug effects* / Q000502:physiology; D012118:Resorcinols / Q000494:pharmacology; D013574:Synaptosomes / Q000187:drug effects / Q000502:physiology; D013997:Time Factors
D065095:Calcineurin Inhibitors; D004075:Diglycerides; D004791:Enzyme Inhibitors; D018691:Excitatory Amino Acid Antagonists; D011722:Pyrethrins; D018094:Receptors, Metabotropic Glutamate; D012118:Resorcinols; C017160:cypermethrin; D016718:Arachidonic Acid; D018698:Glutamic Acid; C079215:3,5-dihydroxyphenylglycine; D016572:Cyclosporine; D015761:4-Aminopyridine; D019703:Calcineurin; D054645:Protein Phosphatase 1; D002118:Calcium; D005998:Glycine