Functional coupling of rat group II metabotropic glutamate receptors to an omega-conotoxin GVIA-sensitive calcium channel in human embryonic kidney 293 cells

Metabotropic glutamate receptors are G protein-coupled receptors that perform a variety of modulatory roles in the central and peripheral nervous systems. The development of receptor subtype-specific agonists/antagonists has lagged far behind the isolation and characterization of receptor cDNAs. Further more, the coupling of specific metabotropic receptors to the various neuronal-specific effector molecules, such as voltage gated Ca2+ channels, has not been well studied. It was recently demonstrated that a rat group II metabotropic receptor (rm-GluR2) is capable of coupling to endogenous N-type Ca2+ channels when heterologously expressed in adult rat sympathetic ganglia neurons. To eventually understand the molecular aspects of metabotropic receptor modulation of the N-type Ca2+ channel, we have transiently expressed both group II receptors in a human embryonic kidney 293 cell line (G1A1) that stably expresses the human alpha 1B-1, alpha 2b, and beta 1-3 Ca2+ channel subunits. rmGluR2 and rmGluR3 modulate the omega-conotoxin GVIA-sensitive Ba2+ currents in G1A1 cells using a voltage-dependent mechanism via an endogenous pertussis toxin-sensitive G protein. Cell-attached "macropatch" recordings demonstrate that modulation by rmGluR2 and rmGluR3 is membrane delimited. This is the first report of Ca2+ channel modulation mediated by rmGluR3. In addition, an extensive pharmacological comparison between rmGluR2 and rmGluR3 reveals that these group II receptors interact with agonists and antagonists in unique ways.