title: The modulation of Ca2+ and K+ channels but not changes in cAMP signaling contribute to the inhibition of glutamate release by cannabinoid receptors in cerebrocortical nerve terminals.
abstract: While cannabinoid receptors activate multiple signaling pathways in the brain, it remains unclear what influence the inhibition of adenylylcyclase has on the inhibition of glutamate release. In cerebrocortical nerve terminals, the cannabinoid receptor agonist WIN55,212-2 reduced KCl-evoked glutamate release through a mechanism that restricted the rise of cytoplasmic free Ca2+, but not the changes in plasma membrane depolarization. These effects were consistent with the inhibition of Ca2+ channels. Furthermore, WIN55,212-2 reduced 4-aminopyridine (4AP) evoked glutamate release to a larger extent by modulating the behavior of both Ca2+ and K(+)-channels. The inhibition of 4AP-evoked release was associated with a decrease in cytoplasmic free Ca2+ and in plasma membrane depolarization that was reverted by the potassium channel blocker, tetraethylammonium. Interestingly, the reduction of KCl- and 4AP-evoked release by WIN55,212-2 was independent of adenylylcyclase activity and did not affect cAMP. Forskolin and the beta-adrenergic receptor increase intrasynaptosomal cAMP and promote a PKA-dependent tetrodotoxin (TTX)-sensitive increase in the spontaneous release of glutamate. These two responses were reduced by WIN55,212-2. However, the glutamate release induced by Sp-8-Br-cAMPS, which directly activated PKA without affecting cAMP, was also similarly reduced by WIN55,212-2. Hence, we conclude that the inhibition of glutamate release by WIN55,212-2 is unrelated to changes in cAMP and that the inhibition of release that a decrease in cAMP might produce is occluded by the activation of additional pathways such as the inhibition of Ca2+ channels and/or the activation of K(+)-channels that strongly depress glutamate release.
authors.affiliation: Departamento de Bioquímica, Facultad de Veterinaria, Universidad Complutense, Madrid 28040, Spain.
authors.forename: María
authors.initials: M
authors.lastname: del Carmen Godino
authors.forename: Magdalena
authors.initials: M
authors.lastname: Torres
authors.forename: José
authors.initials: J
authors.lastname: Sánchez-Prieto
mesh_terms: D000818:Animals; D002121:Calcium Channel Blockers / Q000494:pharmacology; D015220:Calcium Channels / Q000378:metabolism*; D002540:Cerebral Cortex / Q000187:drug effects / Q000378:metabolism; D000242:Cyclic AMP / Q000378:metabolism / Q000502:physiology*; D018698:Glutamic Acid / Q000378:metabolism*; D008297:Male; D026902:Potassium Channel Blockers / Q000494:pharmacology; D015221:Potassium Channels / Q000378:metabolism*; D017729:Presynaptic Terminals / Q000187:drug effects / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D043882:Receptors, Cannabinoid / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*
chemical_list: D002121:Calcium Channel Blockers; D015220:Calcium Channels; D026902:Potassium Channel Blockers; D015221:Potassium Channels; D043882:Receptors, Cannabinoid; D018698:Glutamic Acid; D000242:Cyclic AMP