Protein phosphatase 1 and 2A inhibitors prolong the switch in the control of glutamate release by group I metabotropic glutamate receptors: characterization of the inhibitory pathway.
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 Ca(2+) channels. This inhibitory action was suppressed by addition of the protein kinase C activator 4beta-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.
Sistiaga
A
A
Departamento de Bioquímica, Facultad de Veterinaria, Universidad Complutense, Madrid, Spain.
Sánchez-Prieto
J
J
D015761:4-Aminopyridine / Q000494:pharmacology; D000818:Animals; D001923:Brain Chemistry; D020864:Calcium Channels, N-Type / Q000187:drug effects / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D019204:GTP-Binding Proteins / Q000037:antagonists & inhibitors; D018698:Glutamic Acid / Q000378:metabolism*; D005998:Glycine / Q000031:analogs & derivatives* / Q000494:pharmacology; D008297:Male; D037342:Pertussis Toxin; D015240:Phorbol 12,13-Dibutyrate / Q000494:pharmacology; D010749:Phosphoprotein Phosphatases / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D011188:Potassium / Q000494:pharmacology; D026902:Potassium Channel Blockers; D011493:Protein Kinase C / Q000378:metabolism; D054645:Protein Phosphatase 1; D051381:Rats; D017208:Rats, Wistar; D018094:Receptors, Metabotropic Glutamate / Q000819:agonists / Q000378:metabolism*; D012118:Resorcinols / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects; D013574:Synaptosomes / Q000187:drug effects / Q000378:metabolism*; D010566:Virulence Factors, Bordetella / Q000494:pharmacology
D020864:Calcium Channels, N-Type; D004791:Enzyme Inhibitors; D018691:Excitatory Amino Acid Antagonists; D026902:Potassium Channel Blockers; D018094:Receptors, Metabotropic Glutamate; D012118:Resorcinols; D010566:Virulence Factors, Bordetella; C104077:metabotropic glutamate receptor type 1; D015240:Phorbol 12,13-Dibutyrate; D018698:Glutamic Acid; C079215:3,5-dihydroxyphenylglycine; D015761:4-Aminopyridine; D037342:Pertussis Toxin; D011493:Protein Kinase C; D010749:Phosphoprotein Phosphatases; D054645:Protein Phosphatase 1; D019204:GTP-Binding Proteins; D011188:Potassium; D005998:Glycine