title: Polarized axonal surface expression of neuronal KCNQ channels is mediated by multiple signals in the KCNQ2 and KCNQ3 C-terminal domains.
abstract: The M channels, important regulators of neuronal excitability, are voltage-gated potassium channels composed of KCNQ2-5 subunits. Mutations in KCNQ2 and KCNQ3 cause benign familial neonatal convulsions (BFNC), dominantly inherited epilepsy and myokymia. Crucial for their functions in controlling neuronal excitability, the M channels must be placed at specific regions of the neuronal membrane. However, the precise distribution of surface KCNQ channels is not known. Here, we show that KCNQ2/KCNQ3 channels are preferentially localized to the surface of axons both at the axonal initial segment and more distally. Whereas axonal initial segment targeting of surface KCNQ channels is mediated by ankyrin-G binding motifs of KCNQ2 and KCNQ3, sequences mediating targeting to more distal portion of the axon reside in the membrane proximal and A domains of the KCNQ2 C-terminal tail. We further show that several BFNC mutations of KCNQ2 and KCNQ3 disrupt surface expression or polarized surface distribution of KCNQ channels, thereby revealing impaired targeting of KCNQ channels to axonal surfaces as a BFNC etiology.
authors.affiliation: Departments of Physiology and Biochemistry, Howard Hughes Medical Institute, University of California, San Francisco, CA 94143.
authors.forename: Hee Jung
authors.initials: HJ
authors.lastname: Chung
authors.forename: Yuh Nung
authors.initials: YN
authors.lastname: Jan
authors.forename: Lily Y
authors.initials: LY
authors.lastname: Jan
mesh_terms: D020816:Amino Acid Motifs; D000818:Animals; D017487:Ankyrins / Q000378:metabolism; D001369:Axons / Q000378:metabolism*; D016764:Cell Polarity; D020936:Epilepsy, Benign Neonatal / Q000235:genetics; D015870:Gene Expression; D051658:KCNQ2 Potassium Channel / Q000737:chemistry* / Q000378:metabolism*; D051659:KCNQ3 Potassium Channel / Q000737:chemistry* / Q000378:metabolism*; D009154:Mutation / Q000235:genetics; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D021381:Protein Transport; D051381:Rats; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D015398:Signal Transduction
chemical_list: D017487:Ankyrins; D051658:KCNQ2 Potassium Channel; D051659:KCNQ3 Potassium Channel; D011993:Recombinant Fusion Proteins