Homer proteins regulate coupling of group I metabotropic glutamate receptors to N-type calcium and M-type potassium channels

Group I metabotropic glutamate receptors (mGluR1 and 5) couple to intracell ular calcium pools by a family of proteins, termed Homer, that cross-link t he receptor to inositol trisphosphate receptors. mGluRs also couple to memb rane ion channels via G-proteins. The role of Homer proteins in channel mod ulation was investigated by expressing mGluRs and various forms of Homer in rat superior cervical ganglion (SCG) sympathetic neurons by intranuclear c DNA injection. Expression of cross-linking-capable forms of Homer (Homer 1b , 1c, 2, and 3, termed long forms) occluded group I mGluR-mediated N-type c alcium and M-type potassium current modulation. This effect was specific fo r group I mGluRs. mGluR2 (group II)-mediated inhibition of N-channels was u naltered. Long forms of Homer decreased modulation of N- and M-type current s but did not selectively block distinct G-protein pathways. Short forms of Homer, which cannot self-multimerize (Homer 1a and a Homer 2 C-terminal de letion), did not alter mGluR-ion channel coupling. When coexpressed with lo ng forms of Homer, short forms restored the mGluR1a-mediated calcium curren t modulation in an apparent dose-dependent manner. Homer 2b induced cell su rface clusters of mGluR5 in SCG neurons. Conversely, a uniform distribution was observed when mGluR5 was expressed alone or with Homer short forms. Th ese studies indicate that long and short forms of Homer compete for binding to mGluRs and regulate their coupling to ion channels. In vivo, the immedi ate early Homer 1a is anticipated to enhance ion channel modulation and to disrupt coupling to releasable intracellular calcium pools. Thus, Homer may regulate the magnitude and predominate signaling output of group I mGluRs.