Roles of specific metabotropic glutamate receptor subtypes in regulation of hippocampal CA1 pyramidal cell excitability

R. W. Gereau IV, P. J. Conn

Research output: Contribution to journalArticlepeer-review

140 Scopus citations

Abstract

1. Metabotropic glutamate receptors (mGluRs) are coupled to various second-messenger systems through guanosine 5'-triphospate-binding proteins. To date, at least seven mGluRs have been cloned, and these mGluR subtypes can be divided into three major groups on the basis of similarities in amino acid sequence, coupling to second-messenger cascades in expression systems, and pharmacological profiles. These groups include group I (mGluR1 and mGluR5), group II (mGluR2 and mGluR3), and group III (mGluR4, mGluR6, and mGluR7). 2. On the basis of its selective activation of phosphoinositide hydrolysis in brain slices and its ability to activate mGluR1a expressed in Xenopus oocytes, others have suggested that 3,5-dihydroxyphenylglycine (DHPG) may be selective for group I mGluRs. Consistent with this hypothesis, we report that DHPG also activates mGluR5 expressed in oocytes, whereas it is inactive at mGluR4 and mGluR7 expressed in baby hamster kidney (BHK) cells. The compound (2(S), 1'(R), 2'(R), 3'(R)) - 2 - (2,3 - dicarboxycyclopropyl) glycine (DCG- IV) activates both mGluR2 and mGluR3 at submicromolar concentrations, whereas it is inactive at mGluR4 and mGluR1, suggesting that this compound may be selective for group II mGluRs. Consistent with this hypothesis, we find that DCG-IV does not activate mGluR5 expressed in oocytes and does not activate mGluR7 expressed in BHK cells. These findings suggest that DHPG and DCG-IV are highly selective agonists for group I and group II mGluRs, respectively. 3. Previous studies that have examined the physiological roles of mGluRs have generally used agonists that do not differentiate between the various subtypes. We have performed a detailed pharmacological analysis, including examination of the effects of agonists that are selective for group I (DHPG), group II (DCG-IV), and group III (L-2-amino-4-phosphonobutyric acid) mGluRs, as well as agonist rank orders of potency, to evaluate the roles of the specific mGluR subtypes in mediating the direct excitatory effects of mGluR activation on CA1 pyramidal cells. 4. All of the direct excitatory effects on CA1 pyramidal cells tested, including depolarization, increased input resistance, blockade of the slow afterhyperpolarization, and spike frequency adaptation, have pharmacological profiles that are consistent with mediation by a group I mGluR but not consistent with mediation by group II or III mGluRs. 5. These studies suggest that the direct excitatory effects on CA1 pyramidal cells are mediated by a receptor with group I-like pharmacology, possibly by mGluR5, which is expressed in abundance in CA1 pyramidal cells.

Original languageEnglish
Pages (from-to)122-129
Number of pages8
JournalJournal of neurophysiology
Volume74
Issue number1
DOIs
StatePublished - 1995

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