Rw. Gereau et Pj. Conn, ROLES OF SPECIFIC METABOTROPIC GLUTAMATE-RECEPTOR SUBTYPES IN REGULATION OF HIPPOCAMPAL CA1 PYRAMIDAL CELL EXCITABILITY, Journal of neurophysiology, 74(1), 1995, pp. 122-129
1. Metabotropic glutamate receptors (mGluRs) are coupled to various se
cond-messenger systems through guanosine 5'-triphospate-binding protei
ns. To date, at least seven mGluRs have been cloned, and these mGluR s
ubtypes can be divided into three major groups on the basis of similar
ities in amino acid sequence, coupling to second-messenger cascades in
expression systems, and pharmacological profiles. These groups includ
e group I (mGluR1 and mGluR5), group II (mGluR2 and mGluR3), and group
III (mGluR4, mGluR6, acid mGluR7). 2. On the basis of its selective a
ctivation of phosphoinositide hydrolysis in brain slices and its abili
ty to activate mGluR1a expressed in Xenopus oocytes, others have sugge
sted that 3,5-dihy droxyphenylglycine (DHPG) may be selective for grou
p I mGluRs. Consistent with this hypothesis, we report that DHPG also
activates mGluR5 expressed in oocytes, whereas it is inactive at mGluR
4 and mGluR7 expressed, in baby hamster kidney (BHK) cells. The compou
nd ),2'(R),3'(R))-2-(2,3-dicarboxycyclopropyl)glycine (DCG-IV) activat
es both mGluR2 and mGluR3 at submicromolar concentrations, whereas it
is inactive at mGluR4, and mGluR1, suggesting that this compound may b
e selective for group II mGluRs. Consistent with this hypothesis, we f
ind that DCG-IV does not activate mGluR5 expressed in oocytes and does
not activate mGluR7 expressed in BHK cells. These findings suggest th
at DHPG and DCG-IV are highly selective agonists for group I and group
II mGluRs, respectively. 3. Previous studies that have examined the p
hysiological roles of mGluRs have generally used agonists that do not
differentiate between the various subtypes. We have performed a detail
ed pharmacological analysis, including examination of the effects of a
gonists that are selective for group I (DHPG), group II (DCG-IV), and
group III (L-2-amino-4-phosphonobutyric acid) mGLuRs, as well as agoni
st rank orders of potency, to evaluate the roles of the specific mGluR
subtypes in mediating the direct excitatory effects of mGluR activati
on 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 fre
quency adaptation, have pharmacological profiles that are consistent w
ith mediation by a group I mGluR but not consistent with mediation by
group II or III mGluRs. 5. These studies suggest that the direct excit
atory effects on CA1 pyramidal cells are mediated by a receptor with g
roup I-like pharmacology, possibly by mGluR5, which is expressed in ab
undance in CA1 pyramidal cells.