Presynaptic metabotropic glutamate receptors modulate omega-conotoxin-GVIA-insensitive calcium channels in the rat medulla.
We have previously demonstrated that the metabotropic glutamate receptor (mGluR) agonist (1S,3R)-1 aminocyclopentane-1,3-dicarboxylate (ACPD) presynaptically inhibits evoked glutamatergic EPSCs and GABAergic IPSCs in patch clamped rat nucleus tractus solitarius (NTS) neurons recorded in this slices. The present study investigated the pharmacology of the presynaptic mGluRs, the the voltage dependent Ca2+ channel (VDCC) subtypes supporting neurotransmitter release, and possible interactions between the two. Monosynaptic EPSCs or IPSCs were evoked by electrical stimulation in the region of the tractus solitarius (TS). The effects of the mGluR agonists ACPD, (2S,3S,4S)-alpha-(carboxycyclopropyl)glycine (L-CCG-I) and L-2-amino-4-phosphonobutyrate (AP4) were examined upon EPSCs. The effects of the above compounds and quisqualate (QUIS) were examined upon IPSCs. L-CCG-I proved the most potent inhibitor of EPSCs and IPSCs. The VDCC blockers omega-AGA-IVA (AGA), omega-conotoxin GVIA (GVIA), omega-conotoxin MVIIC (MVIIC) and nimodipine (NIM) were assessed for their ability to inhibit monosynaptic EPSCs and IPSCs. EPSCs were inhibited by GVIA >> AGA > or = MVIIC. IPSCs were inhibited by AGA > or = MVIIC >> GVIA. NIM was without effect on the EPSC or IPSC. The potency of mGluR inhibition of evoked synaptic transmission was assessed in the absence and following treatment with VDCC blockers. mGluR agonists blocked a greater percentage of the EPSC or IPSC following treatment with GVIA, but not the other VDCC antagonists, than under control conditions. We have previously demonstrated that the postsynaptic inhibitory effects of mGluR activation upon GABAA mediated currents can be mimicked by cyclic guanosine monophosphate (cGMP) analogs. The cGMP-dependent protein kinase (PKG) inhibitors H8 and Rp-8-4-chlorophenylthio-guanosine-3',5'-cyclic monophosphorothioate (Rp-cG) blocked mGluR inhibition of GABAA mediated currents without blocking the ability of mGluR agonists to inhibit the IPSC. The effect of L-CCGI was enhanced following treatment with GVIA in the presence of Rp-cG, confirming a presynaptic locus of mGluR mediated inhibition of the IPSC. In contrast, cGMP analogues potentiate postsynaptic responses to glutamate agonists but depress the EPSC. As with the mGluR agonists, the inhibition of the EPSC by cGMP was potentiated following treatment with GVIA. These results suggest that presynaptic mGluR reduce both glutamate release from afferent fibers and GABA release from inhibitory interneurons following electrical stimulation in the region of the TS. Although different VDCCs support the majority of glutamate and GABA release and mGluR effects on release appear to utilize differing intracellular pathways, presynaptic GVIA-insensitive VDCCs are favorably targeted for inhibition by mGluR agonists.
Department of Pharmacological and Physiological Sciences, University of Chicago, IL 60637, USA.
S R
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Glaum
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Miller
D000818:Animals; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D015220:Calcium Channels / Q000187:drug effects / Q000378:metabolism*; D004594:Electrophysiology; D066298:In Vitro Techniques; D015640:Ion Channel Gating / Q000187:drug effects; D008526:Medulla Oblongata / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D010455:Peptides / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D018094:Receptors, Metabotropic Glutamate / Q000819:agonists / Q000037:antagonists & inhibitors / Q000378:metabolism*; D017661:Receptors, Presynaptic / Q000187:drug effects / Q000378:metabolism*; D017552:Solitary Nucleus / Q000166:cytology / Q000187:drug effects / Q000502:physiology; D013569:Synapses / Q000187:drug effects / Q000502:physiology; D009435:Synaptic Transmission / Q000187:drug effects / Q000502:physiology; D020866:omega-Conotoxin GVIA
D002121:Calcium Channel Blockers; D015220:Calcium Channels; D010455:Peptides; D018094:Receptors, Metabotropic Glutamate; D017661:Receptors, Presynaptic; D020866:omega-Conotoxin GVIA