Clustering of Shaker-type K+ channels by interaction with a family of membrane-associated guanylate kinases.

ANCHORING of ion channels at specific subcellular sites is critical for neuronal signalling, but the mechanisms underlying channel localization and clustering are largely unknown (reviewed in ref. 1). Voltage-gated K+ channels are concentrated in various neuronal domains, including presynaptic terminals, nodes of Ranvier and dendrites, where they regulate local membrane excitability. Here we present functional and biochemical evidence that cell-surface clustering of Shaker-subfamily K+ channels is mediated by the PSD-95 family of membrane-associated putative guanylate kinases, as a result of direct binding of the carboxy-terminal cytoplasmic tails to the K+ channel subunits to two PDZ (also known as GLGF or DHR) domains in the PSD-95 protein. The ability of PDZ domains to function as independent modules for protein-protein interaction, and their presence in other junction-associated molecules (such as ZO-1 (ref. 3) and syntrophin), suggest that PDZ-domain-containing polypeptides may be widely involved in the organization of proteins at sites of membrane specialization.