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Identification and characterization of CIP98 as a novel regulator of mGluR6

Group III metabotropic glutamate receptors (mGluRs) –mGluR4, 6, 7 and 8 – couple exclusively to Gαi/o proteins. mGluR6 has a unique role as the primary postsynaptic neurotransmitter receptor in retinal ON bipolar cells, which receive glutamatergic input directly from photoreceptor cells. Activated mGluR6 initiates a signaling cascade through Gαo that results in inhibition of a cation channel and hyperpolarization of ON bipolar cells. To identify potential regulators of mGluR6 signaling, yeast two‐hybrid screens were developed using intracellular regions of the receptor as baits against a rat retinal library. CIP98 (CASK interacting protein, ‘whirlin’) was identified from these screens. CIP98 has 3 PDZ domains and a proline‐rich domain, but little is known about CIP98 function. We verified expression of CIP98 in ON bipolar cells using single cell RT‐PCR. Using a reconstitution system in sympathetic neurons from the rat superior cervical ganglion (SCG), where we have shown mGluR6 modulation of N‐type calcium channels, we found a dose‐dependent shift in the mGluR6 response to agonist when co‐expressed with a CIP98 truncation mutant. Endogenous CIP98 expression in cultured SCG neurons and hippocampal neurons was confirmed, and knock‐down of endogenous CIP98 with siRNA was used to further examine the impact of CIP98 on mGluR6 function. Together, our data suggest that CIP98 directly regulates mGluR6 signaling.