The hippocampus plays an integral role in a number of normal physiological processes and in various pathological conditions. Fast synaptic transmission is modulated by activation of a family of G protein-coupled glutamate receptors, termed metabotropic glutamate receptors (mGluRs), which can serve as autoreceptors at glutamatergic synapses. Evidence suggests that one mGluR subtype, mGluR7, serves as an autoreceptor at the Schaffer collateral-CA1 synapse. Our preliminary data demonstrate that mGluR7-mediated autoreceptor function at this synapse can be inhibited by activation of protein kinase C (PKC) by phorbol esters or A3 adenosine receptor activation. At present, the mechanism by which PKC inhibits mGluR7 autoreceptor function is not known, yet PKC inhibits signalling of group I mGluRs by a direct phosphorylation of the receptor protein. We postulate that PKC inhibits mGluR7-mediated responses by direct phosphorylation of mGluR7. The proposed studies will elucidate the mechanism by which PKC modulates signalling of mGluR7. A series of biochemical and molecular biological studies is proposed to directly test this hypothesis.
