Nature Neuroscience6, 564 - 571 (2003)
Published online: 18 May 2003; | doi:10.1038/nn1062
AKAP150 signaling complex promotes suppression of the M-current by muscarinic agonists
Naoto Hoshi1, 2, Jia-Sheng Zhang1, Miho Omaki3, Takahiro Takeuchi1, Shigeru Yokoyama1, Nicolas Wanaverbecq4, Lorene K Langeberg2, Yukio Yoneda3, John D Scott2, David A Brown4
& Haruhiro Higashida1
1
Department of Biophysical Genetics, Kanazawa University Graduate School of Medicine, 13-1 Takara-machi, Kanazawa, Ishikawa 920-8640, Japan.
2
Howard Hughes Medical Institute and Vollum Institute, Oregon Health and Science University, L474, 3181 SW Sam Jackson Park Road, Portland, Oregon 97201-3098, USA.
3
Department of Molecular Pharmacology, Faculty of Pharmaceutical Sciences, Kanazawa University, 13-1 Takara-machi, Kanazawa, Ishikawa 920-0934, Japan.
4
Department of Pharmacology, University College London, Gower Street, London WC1E 6BT, UK.
Correspondence should be addressed to Naoto Hoshi hoshin@ohsu.edu
M-type (KCNQ2/3) potassium channels are suppressed by activation of Gq/11-coupled receptors, thereby increasing neuronal excitability. We show here that rat KCNQ2 can bind directly to the multivalent A-kinase-anchoring protein AKAP150. Peptides that block AKAP150 binding to the KCNQ2 channel complex antagonize the muscarinic inhibition of the currents. A mutant form of AKAP150, AKAP(A), which is unable to bind protein kinase C (PKC), also attenuates the agonist-induced current suppression. Analysis of recombinant KCNQ2 channels suggests that targeting of PKC through association with AKAP150 is important for the inhibition. Phosphorylation of KCNQ2 channels was increased by muscarinic stimulation; this was prevented either by coexpression with AKAP(A) or pretreatment with PKC inhibitors that compete with diacylglycerol. These inhibitors also reduced muscarinic inhibition of M-current. Our data indicate that AKAP150-bound PKC participates in receptor-induced inhibition of the M-current.
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A), which is unable to bind protein kinase C (PKC), also attenuates the agonist-induced current suppression. Analysis of recombinant KCNQ2 channels suggests that targeting of PKC through association with AKAP150 is important for the inhibition. Phosphorylation of KCNQ2 channels was increased by muscarinic stimulation; this was prevented either by coexpression with AKAP(
