Anchoring proteins confer G protein sensitivity to an inward-rectifier K+ channel through the GK domain

Anchoring proteins cluster receptors and ion channels at postsynaptic membr anes in the brain. They also act as scaffolds for intracellular signaling m olecules including synGAP and NO synthase, Here we report a new function fo r intracellular anchoring proteins: the regulation of synaptic ion channel function. A neuronal G protein-gated inwardly rectifying K+ channel, Kir3.2 c, can not be activated either by M-2-muscarinic receptor stimulation or by G(beta gamma) overexpression. When coexpressed with SAP97, a member of the PSD/SAP anchoring protein family, the channel became sensitive to G protei n stimulation. Although the C-terminus of Kir3.2c bound to the second PDZ d omain of SAP97, functional analyses revealed that the guanylate kinase (GK) domain of SAP97 is crucial for sensitization of the Kir3.2c channel to G p rotein stimulation. Furthermore, SAPAP1/GKAP, which binds specifically to t he GK domain of membrane-associated guanylate kinases, prevented the SAP97- induced sensitization. The function of a synaptic ion channel can therefore be controlled by a network of various intracellular proteins.