Calmodulin dependence of presynaptic metabotropic glutamate receptor signaling

Glutamatergic neurotransmission is controlled by presynaptic metabotropic g lutamate receptors (mGluRs). A subdomain in the intracellular carboxyl-term inal tail of group III mGluRs binds calmodulin and heterotrimeric guanosine triphosphate-binding protein (G protein) beta gamma subunits in a mutually exclusive manner. Mutations interfering with calmodulin binding and calmod ulin antagonists inhibit G protein-mediated modulation of ionic currents by mGluR 7. Calmodulin antagonists also prevent inhibition of excitatory neur otransmission via presynaptic mGluRs. These results reveal a novel mechanis m of presynaptic modulation in which Ca2+-calmodulin is required to release G protein beta gamma subunits from the C-tail of group III mGluRs in order to mediate glutamatergic autoinhibition.