Stimulation of Ca2+‐Activated Non‐specific Cationic Channels by Phospholipase C‐linked Glutamate Receptors in Synaptoneurosomes?

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Abstract
The regulation of intracellular Ca2+ concentration ([Ca2+]i) by glutamate metabotropic receptors (mGluR) was studied in 8‐day‐old rat forebrain synaptoneurosomes using spectrofluorimetric methods. Here we demonstrate that metabotropic glutamate agonists induce in rat brain synaptoneurosomes a Ca2+ influx largely dependent upon the presence of Ca2+ in the external medium. The pharmacological profile of this influx is strongly correlated with the pharmacological profile of the activation of phosphoinositide hydrolysis, i.e. quisqualic acid ∼ 1S,3R‐amino‐1‐dicarboxylate‐1,3 cyclopentane ≅ glutamate. This metabotropic glutamate receptor‐induced Ca2+ influx is insensitive to voltage‐dependent Ca2+ channel antagonists and occurs through a Mn2+ impermeant pathway. The study of the rapid kinetics shows that this influx is triggered after a 300 ms delay compared with that elicited by depolarizing agents and Ca2+ ionophore A23187. In order to assess further if mGluR stimulate this influx through the recruitment of inositol triphosphate (IP3)‐sensitive intracellular Ca2+ stores, we have tested the effect of thapsigargin on membrane potential and intracellular Ca2+ simultaneously. Thapsigargin induces a depolarization of the synaptoneurosomal membrane followed by a massive Ca2+ influx, occurring via a Mn2+ nonpermeant route. This depolarizing effect is sensitive to the presence of the intracellular Ca2+ chelator [1,2‐bis(2‐aminophenoxy)ethane‐N, N, N', N'‐tetraacetoxymethyl ester], and partially sensitive to extracellular Na+, but insensitive to the presence of extracellular Ca2+. Taken together, our data suggest that mGluR stimulate self‐maintained increases of [Ca2+]i in rat forebrain synaptoneurosomes via the activation of a multistep mechanism, sequenced in the following steps: (i) mGluR‐induced IP3 synthesis; (ii) IP3‐stimulated intracellular Ca2+ release; (iii) Ca2+‐activated non‐specific cation channel, leading to local depolarization and a Ca2+ influx; and (iv) activation of Ca2+‐sensitive phospholipase C.

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