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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 cyto-plasmic tails of the K⁺ channel subunits to two PDZ (also known as GLGF or DHR) domains in the PSD-95 protein². The ability of PDZ domains to function as independent modules for protein–protein interaction, and their presence in other junction-associated molecules (such …