QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) All Versions of this Article: mol.105.010975v1 67/6/1840    most recent Submit a response Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Guo, J. Articles by Ikeda, S. R. Search for Related Content PubMed PubMed Citation Articles by Guo, J. Articles by Ikeda, S. R.

Coupling of Metabotropic Glutamate Receptor 8 to N-Type Ca²⁺ Channels in Rat Sympathetic Neurons

Laboratory of Molecular Physiology, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, Maryland

Group III metabotropic glutamate receptors (mGluRs; mGluR4, 6, 7, and 8) couple to the G_i/o-containing G protein heterotrimers and act as autoreceptors to regulate glutamate release, probably by inhibiting voltage-gated Ca²⁺ channels. Although most mGluRs have been functionally expressed in a variety of systems, few studies have demonstrated robust coupling of mGluR8 to downstream effectors. We therefore tested whether activation of mGluR8 inhibited Ca²⁺ channels. Both L-glutamate (L-Glu) and L-2-amino-4-phosphonobutyric acid (L-AP4), a selective agonist for group III mGluRs, inhibited N-type Ca²⁺ current in rat superior cervical ganglion neurons previously injected with a cDNA encoding mGluR8a/b. L-AP4 was 100-fold more potent (IC₅₀ = 0.1 µM) than L-Glu (10 µM), but it had efficacy similar to that of L-Glu (50% maximal inhibition). The potency and efficacy of L-AP4 and L-Glu were similar for both splice variants. Agonist-induced inhibition was abolished by pretreatment with (R,S)--cyclopropyl-4-phosphonophenylglycine, a selective group III mGluR antagonist, and pertussis toxin. Deletion of either a calmodulin (CaM) binding motif in the C terminus or the entire C terminus of mGluR8 did not affect mGluR8-mediated response. Our studies indicate that both mGluR8a and 8b are capable of inhibiting N-type Ca²⁺ channel, suggesting a role as presynaptic autoreceptors to regulate neuronal excitability. The studies also imply that the potential CaM binding domain is not required for the mGluR8-mediated Ca²⁺ channel inhibition and the C terminus of mGluR8a is dispensable for receptor coupling to N-type Ca²⁺ channels.

Address correspondence to: Dr. Stephen R. Ikeda, Laboratory of Molecular Physiology, National Institute on Alcohol Abuse and Alcoholism, Room TS-06, 5625 Fishers Lane, Bethesda, MD 20892-8815. E-mail: sikeda{at}mail.nih.gov

This article has been cited by other articles:

				C. M. Niswender, K. A. Johnson, C. D. Weaver, C. K. Jones, Z. Xiang, Q. Luo, A. L. Rodriguez, J. E. Marlo, T. de Paulis, A. D. Thompson, et al. Discovery, Characterization, and Antiparkinsonian Effect of Novel Positive Allosteric Modulators of Metabotropic Glutamate Receptor 4 Mol. Pharmacol., November 1, 2008; 74(5): 1345 - 1358. [Abstract] [Full Text] [PDF]

				C. M. Niswender, K. A. Johnson, Q. Luo, J. E. Ayala, C. Kim, P. J. Conn, and C. D. Weaver A Novel Assay of Gi/o-Linked G Protein-Coupled Receptor Coupling to Potassium Channels Provides New Insights into the Pharmacology of the Group III Metabotropic Glutamate Receptors Mol. Pharmacol., April 1, 2008; 73(4): 1213 - 1224. [Abstract] [Full Text] [PDF]

				J. Guo, D. J. Williams, H. L. Puhl III, and S. R. Ikeda Inhibition of N-Type Calcium Channels by Activation of GPR35, an Orphan Receptor, Heterologously Expressed in Rat Sympathetic Neurons J. Pharmacol. Exp. Ther., January 1, 2008; 324(1): 342 - 351. [Abstract] [Full Text] [PDF]

				J. Guo, H. Chen, H. L. Puhl III, and S. R. Ikeda Fluorophore-assisted light inactivation produces both targeted and collateral effects on N-type calcium channel modulation in rat sympathetic neurons J. Physiol., October 15, 2006; 576(2): 477 - 492. [Abstract] [Full Text] [PDF]