Roles of Specific Metabotropic Glutamate Receptor Subtypes in Regulation of
Hippocampal CA1 Pyramidal Cell Excitability.
Gereau, Robert W., and P. Jeffrey Conn.
Department of Pharmacology and Program in Neuroscience, Emory University
School of Medicine. Atlanta, GA 30322.
APStracts 2:0069N, 1995.
SUMMARY AND CONCLUSIONS
1. Metabotropic glutamate receptors (mGluRs) are coupled to various second
messenger systems through GTP-binding proteins. To date, at least seven mGluRs
have been cloned (Schoepp 1994, Suzdak et al, 1994), and these mGluR subtypes
can be divided into three major groups based on similarities in amino acid
sequence, coupling to second messenger cascades in expression systems, and
pharmacological profiles. These groups include group I (mGluR1 and 5), group
II (mGluR2 and 3) and group III (mGluR4, 6, and 7). . Based on its selective
activation of phosphoinositide hydrolysis in brain slices and its ability to
activate mGluR1a expressed in Xenopus oocytes, others have suggested the
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 while it is inactive at mGluR4 and mGluR7 expressed in
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 while 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
which are selective for Group I (DHPG), Group II (DCG-IV), and Group III (L-
AP4) 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 (AHP), 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.
Received 28 November 1994; accepted in final form 3 March 1995.
APS Manuscript Number J739-4.
Article publication pending J. Neurophysiol.
ISSN 1080-4757 Copyright 1995 The American Physiological Society.
Published in APStracts on 3 April 1995.