title: Activation of m1 muscarinic acetylcholine receptor induces surface transport of KCNQ channels through a CRMP-2-mediated pathway.
abstract: Neuronal excitability is strictly regulated by various mechanisms, including modulation of ion channel activity and trafficking. Stimulation of m1 muscarinic acetylcholine receptor (also known as CHRM1) increases neuronal excitability by suppressing the M-current generated by the Kv7/KCNQ channel family. We found that m1 muscarinic acetylcholine receptor stimulation also triggers surface transport of KCNQ subunits. This receptor-induced surface transport was observed with KCNQ2 as well as KCNQ3 homomeric channels, but not with Kv3.1 channels. Deletion analyses identified that a conserved domain in a proximal region of the N-terminal tail of KCNQ protein is crucial for this surface transport--the translocation domain. Proteins that bind to this domain were identified as α- and β-tubulin and collapsin response mediator protein 2 (CRMP-2; also known as DPYSL2). An inhibitor of casein kinase 2 (CK2) reduced tubulin binding to the translocation domain, whereas an inhibitor of glycogen synthase kinase 3 (GSK3) facilitated CRMP-2 binding to the translocation domain. Consistently, treatment with the GSK3 inhibitor enhanced receptor-induced KCNQ2 surface transport. M-current recordings from neurons showed that treatment with a GSK3 inhibitor shortened the duration of muscarinic suppression and led to over-recovery of the M-current. These results suggest that m1 muscarinic acetylcholine receptor stimulates surface transport of KCNQ channels through a CRMP-2-mediated pathway.
authors.affiliation: State Key Laboratory of Natural and Biomimetic Drugs, Department of Pharmacology, School of Basic Medical Sciences, Peking University Health Science Center, and Beijing Key Laboratory of Tumor Systems Biology, Peking University, Beijing 100191, China Department of Pharmacology, University of California, Irvine, 360 Med Surge II, Irvine, CA 92617, USA.
authors.forename: Ling
authors.initials: L
authors.lastname: Jiang
authors.affiliation: Department of Pharmacology, University of California, Irvine, 360 Med Surge II, Irvine, CA 92617, USA.
authors.forename: Anastasia
authors.initials: A
authors.lastname: Kosenko
authors.affiliation: Department of Physiology and Biophysics, University of California, Irvine, D340 Medical Science I, Irvine, CA 92697, USA.
authors.forename: Clinton
authors.initials: C
authors.lastname: Yu
authors.affiliation: Department of Physiology and Biophysics, University of California, Irvine, D340 Medical Science I, Irvine, CA 92697, USA.
authors.forename: Lan
authors.initials: L
authors.lastname: Huang
authors.affiliation: State Key Laboratory of Natural and Biomimetic Drugs, Department of Pharmacology, School of Basic Medical Sciences, Peking University Health Science Center, and Beijing Key Laboratory of Tumor Systems Biology, Peking University, Beijing 100191, China.
authors.forename: Xuejun
authors.initials: X
authors.lastname: Li
authors.affiliation: Department of Pharmacology, University of California, Irvine, 360 Med Surge II, Irvine, CA 92617, USA Department of Physiology and Biophysics, University of California, Irvine, D340 Medical Science I, Irvine, CA 92697, USA nhoshi@uci.edu.
authors.forename: Naoto
authors.initials: N
authors.lastname: Hoshi
mesh_terms: D000109:Acetylcholine / Q000378:metabolism*; D000595:Amino Acid Sequence; D000818:Animals; D016466:CHO Cells; D003412:Cricetulus; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism*; D051658:KCNQ2 Potassium Channel / Q000378:metabolism*; D008969:Molecular Sequence Data; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D009474:Neurons / Q000378:metabolism*; D043643:Receptor, Muscarinic M1 / Q000378:metabolism*
chemical_list: D036341:Intercellular Signaling Peptides and Proteins; D051658:KCNQ2 Potassium Channel; C496914:KCNQ2 protein, human; D009419:Nerve Tissue Proteins; D043643:Receptor, Muscarinic M1; C095114:collapsin response mediator protein-2; D000109:Acetylcholine
keywords: CK2; CRMP-2; Channel trafficking; GSK3; KCNQ2; Muscarinic acetylcholine receptor