The inhibition of glutamate release by metabotropic glutamate receptor 7 affects both [Ca2+]c and cAMP. Evidence for a strong reduction of Ca2+ entry in single nerve terminals Journal Article


Author(s): Millán, Carmelo; Luján, Rafael; Shigemoto, Ryuichi; Sánchez-Prieto, José
Article Title: The inhibition of glutamate release by metabotropic glutamate receptor 7 affects both [Ca2+]c and cAMP. Evidence for a strong reduction of Ca2+ entry in single nerve terminals
Affiliation
Abstract: Metabotropic glutamate receptors (mGluRs) from group III reduce glutamate release. Because these receptors reduce cAMP levels, we explored whether this signaling pathway contributes to release inhibition caused by mGluRs with low affinity for L-2-amino-4-phosphonobutyrate (L-AP4). In biochemical experiments with the population of cerebrocortical nerve terminals we find that L-AP4 (1 mM) inhibited the Ca2+dependent-evoked release of glutamate by 25%. This inhibitory effect was largely prevented by the pertussis toxin but was insensitive to inhibitors of protein kinase C bisindolylmaleimide and protein kinase A H-89. Furthermore, this inhibition was associated with reduction in N-type Ca2+ channel activity in the absence of any detectable change in cAMP levels. In the presence of forskolin, however, L-AP4 decreased the levels of cAMP. The activation of this additional signaling pathway was very efficient in counteracting the facilitation of glutamate release induced either by forskolin or the β-adrenergic receptor agonist isoproterenol. Imaging experiments to measure Ca2+ dynamics in single nerve terminals showed that L-AP4 strongly reduced the Ca2+ response in 28% of the nerve terminals. Moreover, immunochemical experiments showed that 25-35% of the nerve terminals that were immunopositive to synaptophysin were also immunoreactive to the low affinity L-AP4-sensitive mGluR7. Then, mGluR7 mediates the inhibition of glutamate release caused by 1 mM L-AP4, primarily by a strong inhibition of Ca2+ channels, although high cAMP uncovers the receptor ability to decrease cAMP.
Keywords: Calcium; Glutamic Acid; unclassified drug; Sodium channel; metabotropic receptor; calcium channel; 2 amino 4 phosphonobutyric acid; beta adrenergic receptor stimulating agent; bisindolylmaleimide; cyclic AMP; cyclic AMP dependent protein kinase; forskolin; isoprenaline; metabotropic receptor 7; n [2 (4 bromocinnamylamino)ethyl] 5 isoquinolinesulfonamide; pertussis toxin; protein kinase C inhibitor; synaptophysin
Journal Title: Journal of Biological Chemistry
Volume: 277
Issue 16
ISSN: 1083-351X
Publisher: American Society for Biochemistry and Molecular Biology  
Date Published: 2002-04-19
Start Page: 14092
End Page: 14101
DOI: 10.1074/jbc.M109044200
Open access: no