KRIP6: A novel BTB/kelch protein regulating function of kainate receptors

Whereas many interacting proteins have been identified for AMPA and NMDA glutamate receptors, fewer are known to directly bind and regulate function of kainate receptors. Using a yeast two-hybrid screen for interacting partners of the C-terminal domain of GluR6a, we identified a novel neuronal protein of the BTB/kelch family, KRIP6. KRIP6 binds to the GluR6a C-terminal domain at a site distinct from the PDZ-binding motif and it co-immunoprecipitates with recombinant and endogenous GluR6. Co-expression of KRIP6 alters GluR6 mediated currents in a heterologous expression system reducing peak current amplitude and steady-state desensitization, without affecting surface levels of GluR6. Endogenous KRIP6 is widely expressed in brain and overexpression of KRIP6 reduces endogenous kainate receptor-mediated responses evoked in hippocampal neurons. Taken together, these results suggest that KRIP6 can directly regulate native kainate receptors and provide the first evidence for a BTB/kelch protein in direct functional regulation of a mammalian glutamate receptor.