We report a novel multivalent PDZ domain protein, CIPP (for channel- interacting PDZ domain protein), which is expressed exclusively in brain and kidney. Within the brain, the highest CIPP mRNA levels were found in neurons of the cerebellum, inferior colliculus, vestibular nucleus, facial nucleus, and thalamus. Furthermore, we identified the inward rectifier K+ (Kir) channel, Kir4.1 (also called 'Kir1.2'), as a cellular CIPP ligand. Among several other Kir channels tested, only the closely related Kir4.2 (or 'Kir1.3') also interacted with CIPP. In addition, specific PDZ domains within CIPP associated selectively with the C-termini of N-methyl-D-aspartate subtypes of glutamate receptors, as well as neurexins and neuroligins, cell surface molecules enriched in synaptic membranes. Thus, CIPP may serve as a scaffold that brings structurally diverse but functionally connected proteins into close proximity at the synapse. The functional consequences of CIPP expression on Kir4.1 channels were studied using whole-cell voltage clamp techniques in Kir4.1 transfected COS-7 cells. On average, Kir4.1 current densities were doubled by cotransfection with CIPP.
Bibliographical noteFunding Information:
We thank Drs. Richard Smeyne and Dennis Rice for helpful discussion of neuroanatomical data and Drs. Jim Morgan and Michi Yuzaki for critically reading the manuscript. This work was supported in part by NIH Cancer Center Support CORE Grant P30 CA21765 and by the American Lebanese Syrian Associated Charities (ALSAC).