The metabotropic glutamate receptor mGlu7 activates phospholipase C, translocates munc-13-1 protein, and potentiates glutamate release at cerebrocortical nerve terminals.
At synaptic boutons, metabotropic glutamate receptor 7 (mGlu7 receptor) serves as an autoreceptor, inhibiting glutamate release. In this response, mGlu7 receptor triggers pertussis toxin-sensitive G protein activation, reducing presynaptic Ca(2+) influx and the subsequent depolarization evoked release. Here we report that receptor coupling to signaling pathways that potentiate release can be seen following prolonged exposure of nerve terminals to the agonist l-(+)-phosphonobutyrate, l-AP4. This novel mGlu7 receptor response involves an increase in the release induced by the Ca(2+) ionophore ionomycin, suggesting a mechanism that is independent of Ca(2+) channel activity, but dependent on the downstream exocytotic release machinery. The mGlu7 receptor-mediated potentiation resists exposure to pertussis toxin, but is dependent on phospholipase C, and increased phosphatidylinositol (4,5)-bisphosphate hydrolysis. Furthermore, the potentiation of release does not depend on protein kinase C, although it is blocked by the diacylglycerol-binding site antagonist calphostin C. We also found that activation of mGlu7 receptors translocate the active zone protein essential for synaptic vesicle priming, munc13-1, from soluble to particulate fractions. We propose that the mGlu7 receptor can facilitate or inhibit glutamate release through multiple pathways, thereby exerting homeostatic control of presynaptic function.
Martín
Ricardo
R
Departamento de Bioquímica, Facultad de Veterinaria, Universidad Complutense, 28040 Madrid, Spain.
Durroux
Thierry
T
Ciruela
Francisco
F
Torres
Magdalena
M
Pin
Jean-Philippe
JP
Sánchez-Prieto
José
J
D000818:Animals; D002118:Calcium / Q000737:chemistry; D004075:Diglycerides / Q000737:chemistry; D018698:Glutamic Acid / Q000378:metabolism*; D006868:Hydrolysis; D015759:Ionomycin / Q000494:pharmacology; D007476:Ionophores; D008297:Male; D008954:Models, Biological; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D009474:Neurons / Q000378:metabolism*; D019269:Phosphatidylinositol 4,5-Diphosphate; D018129:Phosphatidylinositol Phosphates / Q000737:chemistry; D051381:Rats; D017208:Rats, Wistar; D018094:Receptors, Metabotropic Glutamate / Q000378:metabolism*; D010738:Type C Phospholipases / Q000737:chemistry / Q000378:metabolism*
D004075:Diglycerides; D007476:Ionophores; D009419:Nerve Tissue Proteins; D019269:Phosphatidylinositol 4,5-Diphosphate; D018129:Phosphatidylinositol Phosphates; D018094:Receptors, Metabotropic Glutamate; C103912:Unc13a protein, rat; C102719:metabotropic glutamate receptor 7; D018698:Glutamic Acid; D015759:Ionomycin; D010738:Type C Phospholipases; D002118:Calcium