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

doi:10.1093/emboj/19.1.78

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

Hiroshi Hibino, Atsushi Inanobe, Masayuki Tanemoto, Akikazu Fujita, Katsumi Doi, Takeshi Kubo, Yutaka Hata, Yoshimi Takai² and Yoshihisa Kurachi

Departments of Pharmacology II, ¹ Otolaryngology and ³ Molecular Biology and Biochemistry, Graduate School of Medicine, Osaka University, 2-2, Yamada-oka, Suita, Osaka 565-0871 and ² Takai Biotimer Project, ERATO, Japan Science and Technology Corporation, c/o JCR Pharmaceuticals Co. Ltd, 2-2-10 Murotani, Nishi-ku Kobe 651-2241, Japan
⁴ Corresponding author
e-mail: ykurachi{at}pharma2.med.osaka-u.ac.jp

Anchoring proteins cluster receptors and ion channels at postsynaptic membranes in the brain. They also act as scaffolds forintracellular signaling molecules including synGAP and NO synthase.Here we report a new function for intracellular anchoring proteins:the regulation of synaptic ion channel function. A neuronal G protein-gatedinwardly rectifying K⁺ channel, Kir3.2c, can not be activated either by M₂-muscarinicreceptor stimulation or by G overexpression. Whencoexpressed with SAP97, a member of the PSD/SAP anchoring proteinfamily, the channel became sensitive to G protein stimulation.Although the C-terminus of Kir3.2c bound to the second PDZ domainof SAP97, functional analyses revealed that the guanylate kinase(GK) domain of SAP97 is crucial for sensitization of the Kir3.2cchannel to G protein stimulation. Furthermore, SAPAP1/GKAP, whichbinds specifically to the GK domain of membrane-associated guanylatekinases, prevented the SAP97-induced sensitization. The functionof a synaptic ion channel can therefore be controlled by a networkof various intracellular proteins.