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

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 approximately equal to 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) Ca(2+)-activated non-specific cation channel, leading to local depolarization and a Ca2+ influx; and (iv) activation of Ca(2+)-sensitive phospholipase C.

Prenatal Ethanol Exposure Reduces mGluR5 Receptor Number and Function in the Dentate Gyrus of Adult Offspring

“…This interpretation does not preclude the possibility that fetal ethanol exposure may have altered other mGluR-mediated responses that regulate neurotransmitter release. Other mGluR-stimulated PLC-/PKCdependent mechanisms that affect neurotransmitter release include IP 3 -triggered release of internal calcium stores (Vignes et al, 1995), decreased permeability of potassium channels that antagonize voltage-dependent calcium entry into nerve terminals (Abdul-Ghani et al, 1996;Gerber and Gahwiler, 1994;Luthi et al, 1996), and inhibition of group II or group III mGluRs that mediate decreased N-and P-type voltage-sensitive calcium channel permeability at nerve terminals (Herrero et al, 1996;Macek et al, 1998). Prenatal ethanol exposure might also affect mGluR-stimulated phospholipase D (PLD)-dependent generation of arachidonic acid (Boss and Conn, 1992;Pellegrini-Giampietro et al, 1996).…”

NMDA receptor dependence of mGlu‐mediated depression of synaptic transmission in the CA1 region of the rat hippocampus

“…The reciprocal facilitatory interaction also occurs postsynaptically since activation of group I mGlu receptors potentiates depolarization induced by NMDA in the hippocampus (Fitzjohn et al, 1996). A Ca2+-dependence in mGlu-stimulated phosphoinositide breakdown in synaptosomes has been demonstrated (Vignes et al, 1995a) so it is also possible that NMDA and mGlu receptor interactions can occur presynaptically.…”

Involvement of transient receptor potential‐like channels in responses to mGluR‐I activation in midbrain dopamine neurons

“…Complex interactions between group I metabotropic glutamate receptors (mGluR‐I), intracellular Ca 2+ stores and Ca 2+ ‐permeable cation channels in the plasma membrane of neurons have been identified in the cortex, hippocampus and cerebellum (Linden et al ., 1994; Vignes et al ., 1995; Abdul‐Ghani et al ., 1996; Fagni et al ., 2000; Nakamura et al ., 2000; Gee et al ., 2003).…”