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Modulation of Voltage-Gated K Channels by the Sodium Channel Β1 Subunit

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Modulation of Voltage-Gated K Channels by the Sodium Channel Β1 Subunit Modulation of voltage-gated K+ channels by the sodium channel β1 subunit Hai M. Nguyena, Haruko Miyazakib, Naoto Hoshic, Brian J. Smithd, Nobuyuki Nukinab, Alan L. Goldine, and K. George Chandya,1 Departments of aPhysiology and Biophysics, cPharmacology, and eMicrobiology and Molecular Genetics, School of Medicine, University of California, Irvine, CA 92697; bLaboratory for Structural Neuropathology, RIKEN Brain Science Institute, Wako-shi, Saitama 351-0198, Japan; and dLa Trobe Institute for Molecular Science, La Trobe University, Melbourne, VIC 3086, Australia Edited* by Michael D. Cahalan, University of California, Irvine, CA, and approved September 26, 2012 (received for review June 1, 2012) β – Voltage-gated sodium (NaV) and potassium (KV) channels are critical Here, we examined whether the NaV 1 KV4.x interaction was components of neuronal action potential generation and propaga- specific for this family of KV channels, or whether NaVβ1 could β SCN1b tion. Here, we report that NaV 1 encoded by , an integral interact and modulate the functions of other families of KV chan- subunit of NaV channels, coassembles with and modulates the bio- nels in mammals. We selected three families of KV channels (KV1, physical properties of KV1andKV7 channels, but not KV3 channels, in KV3, and KV7) for these studies. We report that NaVβ1modulates fi β an isoform-speci c manner. Distinct domains of NaV 1 are involved the function of KV1.1, KV1.2, KV1.3, KV1.6, and KV7.2 channels, in modulation of the different KV channels. Studies with channel but not KV3.1 channels, in an isoform-specific manner. Through chimeras demonstrate that NaVβ1-mediated changes in activation the use of chimeric and mutational strategies we identified regions kinetics and voltage dependence of activation require interaction in NaVβ1 and KV channels required for channel modulation, and of NaVβ1 with the channel’s voltage-sensing domain, whereas docking simulations suggest a molecular model of the interaction of changes in inactivation and deactivation require interaction with the two proteins. the channel’s pore domain. A molecular model based on docking studies shows NaVβ1 lying in the crevice between the voltage-sens- Results fi ing and pore domains of KV channels, making signi cant contacts NaVβ1 Interacts with and Modulates KV1.x Channels. We examined with the S1 and S5 segments. Cross-modulation of NaV and KV chan- the ability of NaVβ1 to modulate activation kinetics, voltage β fl nels by NaV 1 may promote diversity and exibility in the overall dependence of activation and deactivation of KV1.x channels control of cellular excitability and signaling. expressed in mammalian cells or in Xenopus oocytes. In Xenopus oocytes, NaVβ1 accelerated KV1.2 activation, shifted the voltage colocalization | gating | voltage-gated ion channels | patch-clamp | dependence of activation in the hyperpolarized direction and sped accessory subunit up the fast component of deactivation (τfast at −60 mV) (Fig. 1 A– C). In mammalian cells, KV1.2 exhibited use-dependent activation equential opening and closing of central nervous system (CNS) (i.e., successive depolarizing pulses progressively increase the am- NEUROSCIENCE voltage-gated sodium (Na ) and potassium (K ) channels plitude of the KV1.2 current and speed up activation), a unique S V V β fi mediate the depolarization phase (1) and repolarization phase (2, property of this channel (16). NaV 1signi cantly accelerated KV1.2 τ fi 3), respectively, of neuronal action potentials. Although intrinsic activation ( fast at +40 mV) at the rst pulse and to a lesser extent at the ninth pulse (Fig. 1D). Coprecipitation experiments demon- domains within the NaV α subunits underlie voltage-dependent strated that NaVβ1 (dual-tagged at the C terminus with V5 and gating properties and sodium-specific permeation, five NaVβ sub- His ×)andmouseK 1.2 (FLAG-tagged at the C terminus) coas- units (β1, β1B, β2, β3, β4) assemble with and modulate inactivation 6 V sembled when heterologously expressed in mammalian cells (Fig. kinetics and the voltage dependence of activation and inactivation E α β 1 ). Furthermore, immunostaining experiments on normal mouse of NaV subunits (1, 4). In addition, these NaV subunits function β fi brain showed KV1.2 colocalization with NaV 1 in the axon initial in cell adhesion and contribute to neuronal migration, path nding, segment of neurons in the cerebral cortex (Fig. 1F)butnotinnodes – and fasciculation (4 8). Given their ubiquitous roles and distri- of Ranvier (Fig. S1A). bution in the CNS, Na β subunits play a major role in fine-tuning V KV1.1 and KV1.3 had a different staining pattern and did not of action potential generation, propagation, and frequency. Subtle colocalize with NaVβ1 in normal mouse brain (Fig. S1 B and C). changes to their function have resulted in a range of detrimental However, these channels may colocalize with NaVβ1 in de- neurological diseases in humans such as genetic epilepsy with fe- myelinating diseases where their distribution is altered (17–19). brile seizures plus (GEFS+), Dravet syndrome (severe myoclonic We therefore tested the effect of NaVβ1onKV1.1, KV1.3, and epilepsy of infancy), temporal lobe epilepsy, febrile seizures, and KV1.6 channels (Table S1). NaVβ1 shifted the voltage depen- decreased responsiveness to the anticonvulsant drugs carbamaze- dence of activation of KV1.1 by ∼4 mV in the hyperpolarized pine and phenytoin (7–12). direction and it slowed deactivation (τfast) of the channel without A–C β fi KV channels are important contributors to action potential re- affecting its activation kinetics (Fig. 2 ). NaV 1 signi cantly Xenopus D polarization. KV channels in mammals are encoded by 40 genes accelerated activation of KV1.3 in oocytes (Fig. 2 ) and grouped into 12 subfamilies (KV1–KV12). NaVβ1, which was pre- viously thought to be specific for NaV channels, was recently shown Author contributions: H.M.N. and K.G.C. designed research; H.M.N., H.M., N.H., B.J.S., and to coassemble with and modulate the properties of the KV4.x – β N.N. performed research; B.J.S. and A.L.G. contributed new reagents/analytic tools; H.M.N., subfamily of channels (13 15). In the rodent heart, NaV 1 copre- H.M., N.H., B.J.S., N.N., and K.G.C. analyzed data; and H.M.N., B.J.S., and K.G.C. wrote cipitates with KV4.3, and in heterologous expression systems it the paper. increases the amplitude of the KV4.3 current and speeds up acti- The authors declare no conflict of interest. vation (14, 15). In the rodent brain, NaVβ1 coprecipitates with *This Direct Submission article had a prearranged editor. KV4.2, and in heterologous expression systems it enhances surface Freely available online through the PNAS open access option. expression of the channel and increases current amplitude (13). 1To whom correspondence should be addressed. E-mail: [email protected]. β fi Genetic knockout of NaV 1 in mice prolongs action potential ring This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10. in pyramidal neurons through its action on KV4.2 (13). 1073/pnas.1209142109/-/DCSupplemental. www.pnas.org/cgi/doi/10.1073/pnas.1209142109 PNAS | November 6, 2012 | vol. 109 | no. 45 | 18577–18582 Downloaded by guest on September 29, 2021 Fig. 1. Activation kinetics at +40 mV (A, gray hatched area in pulse protocol represents first 30 ms analyzed), voltage dependence of activation (B) (mean ± SEM), and deactivation (C, gray hatched area in pulse protocol represents last 10 ms analyzed) of KV1.2 channels expressed in Xenopus oocytes in the presence or absence of NaVβ1(n ≥ 7). Only currents of comparable amplitude between channel-alone, channel plus NaVβ1, were selected for analysis. (D)KV1.2 stably expressed in L929 fibroblasts exhibits use-dependent activation when repetitive depolarizing pulses at +40mV are administered at 1-s intervals. Average normalized current traces show NaVβ1 speeds up activation of KV1.2 at the first pulse and to a lesser extent at the ninth pulse (KV1.2, n =6;KV1.2 + NaVβ1, n = 9 cells). (E) Western blot of coprecipitation experiment in transfected HEK cells showing that KV1.2 and NaVβ1 coassemble. (F) Mouse cerebral cortex immunostained for KV1.2 (green; Left) and NaVβ1 (red; Center), showing colocalization in the axon initial segment in the merged image (Right). in mammalian cells (Fig. S2F) but had no effect on KV1.3’s axon initial segment and at nodes of Ranvier (25). In mammalian voltage dependence of activation or deactivation kinetics (Fig. 2 cells, NaVβ1 coassembled with FLAG-tagged KV7.2 (Fig. 2M), and E and F). NaVβ1 significantly reduced cumulative inactivation of it slowed the channel’s activation at moderate depolarization vol- KV1.3 (Fig. S2 A–C), a unique property of KV1.3 where successive tages (Fig. 2N, Fig. S4) and altered current measured at different 1- depolarizing pulses cause a progressive diminution in the ampli- s prepulse potentials (Fig. 2O). These data together with those tude of the KV1.3 current as channels accumulate in the C-type presented in Fig. 1 and in the literature (13–15) demonstrate that inactivated state (18). His-tagged NaVβ1 complexes with and NaVβ1 modulates KV1.1, KV1.2, KV1.3, KV1.6, KV4.2, KV4.3, and accelerates activation of KV1.3 in mammalian cells and Xenopus KV7.2, but not KV3.1, each in a unique fashion. oocytes (Fig. S2 D–F). NaVβ1 slowed KV1.6’s activation, shifted its β voltage dependence of activation in the depolarized direction, and Distinct Domains of NaV 1 Are Involved in KV Channel Modulation. β significantly increased the amplitude of the KV1.6 tail current, but NaV 1 and myelin zero (P0), the major protein in peripheral nerve had no effect on the channel’s deactivation kinetics (Fig.
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