mGluR7 inhibits glutamate release through a PKC‐independent decrease in the activity of P/Q‐type Ca²⁺ channels and by diminishing cAMP in hippocampal nerve terminals

Abstract

The modulation of calcium channels by metabotropic glutamate receptors (mGluRs) is a key event in the fine-tuning of neurotransmitter release. Here we report that, in hippocampal nerve terminals from adult rats, the inhibition of glutamate release by the group III mGluR agonist L-2-amino-4-phosphonobutyrate (L-AP4) is largely mediated by mGluR7. In this preparation, P/Q-type Ca(2+) channels support the major component of glutamate release while the remaining release is supported by N-type Ca(2+) channels. The release associated with P/Q channels was modulated by mGluR7, either in the presence of omega-conotoxin-GVIA or after decreasing the extracellular Ca(2+) concentration [Ca(2+)](o) to abolish the contribution of N-type Ca(2+) channels. Under these conditions, L-AP4 (1 mm) reduced the evoked glutamate release by 35 +/- 2%. This inhibition was largely prevented by pertussis toxin, but it was insensitive to inhibitors of protein kinase C (bisindolylmaleimide) and protein kinase A (H-89). Furthermore, this inhibition was associated with a reduction in the Ca(2+) influx mediated by P/Q channels in the absence of any detectable change in cAMP levels. However, L-AP4 decreased the levels of cAMP in the presence of forskolin. The activation of this additional signalling pathway was very efficient in counteracting the facilitation of glutamate release induced by forskolin. Thus, mGluR7 mediates the inhibition of glutamate release at hippocampal nerve terminals primarily by inhibiting P/Q-type Ca(2+) channels, although augmenting the levels of cAMP reveals the ability of the receptor to decrease cAMP.

Group III mGluR regulation of synaptic transmission at the SC-CA1 synapse is developmentally regulated

“…Thus, agonist activity of this compound at mGluR7 could depend on the G proteins or second messenger systems that are activated in a particular cell type or on other cell or pathway-specific factors. Previous studies have led to the suggestion that activation of mGluR7 leads to inhibition of P/ Q-type calcium channel activity in hippocampal nerve terminals by βγ subunits (Martin et al, 2007;Perroy et al, 2000). Since activation of GIRK channels also occurs through activation of βγ subunits (Saugstad et al, 1996), it is interesting that we observed a correlation between the lack of effect of AMN082 in a cell-based system that relies upon βγ-mediated signaling after mGluR7 activation and synaptic transmission.…”

Partial compensation for N‐type Ca2+ channel loss by P/Q‐type Ca2+ channels underlines the differential release properties supported by these channels at cerebrocortical nerve terminals

“…Thus, the dependency of release on [Ca 2+ ] o seems to be an intrinsic property of the channel, probably related to the distance of N‐type channels from release sites, as revealed by the greater sensitivity of N‐type channel‐mediated release to Ca 2+ chelators (Wu et al. , 1999; Martín et al. , 2007).…”

Interneuronal calcium channel abnormalities in posttraumatic epileptogenic neocortex

“…5). Compensatory mechanisms, if present, would not necessarily restore physiological synaptic transmission, as P/Q- and N-type channels have contrasting functional properties that might translate to different roles in transmitter release (Zhang et al, 1996; Wu et al, 1999; Martín et al, 2007; Zaitsev et al, 2007). In contrast to the decreased inhibitory connectivity (Faria and Prince, 2010; Jin et al 2011) and N-channel density (Fig.…”