Pii: S0306-4522(98)00718-0
نویسنده
چکیده
Episodic ataxia type 1 is a rare, autosomal dominant neurological disorder caused by missense mutations of the Kv1.1 gene from the Shaker K channel subfamily. To study the functional effects of the disease-causing mutations in a robust K channel background, we introduced seven different episodic ataxia type 1 substitutions into the corresponding, conserved residues of the Shaker K channel. K channel currents expressed in Xenopus oocytes were studied by electrophysiology. All episodic ataxia type 1 mutations produced functional K channels. In a Shaker N-terminal deletion mutant with fast inactivation removed, current amplitudes were significantly reduced in channels harboring an episodic ataxia type 1 mutation. Six of the seven mutations also showed depolarizing shifts (19 to 136 mV) in the conductance voltage dependence. One mutation (F307I) shifted the midpoint of the conductance–voltage relationship by 23 mV in the hyperpolarizing direction. Episodic ataxia type 1 mutations were also expressed in ShakerH4 with intact N-terminal inactivation. In this construct, current amplitudes for episodic ataxia type 1 mutants were not significantly different from wild-type channels. All mutations altered the voltage range of steady-state inactivation; most changes were coupled to the changes in activation gating. Some episodic ataxia type 1 mutants also caused significant changes in the kinetics of N-type (F307I, E395D) or C-type (F307I, E395D, V478A) inactivation. These results suggest that episodic ataxia type 1 mutations may change K channel function by two mechanisms: (i) reduced channel expression and (ii) altered channel gating. q 1999 IBRO. Published by Elsevier Science Ltd.
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D. L U P I , * t H. M. COOPER,J; A. F R O E H L I C H , * L. S T A N D F O R D , § M. A. McCALL!§ and R. G. F O S T E R * ¶ *Department of Biology, Imperial College of Science, Technology and Medicine, Prince Consort Road, London SW7 2BB, U.K. tCentro Marino Internazionale (IMC), Torregrande-Oristano, Italy ~Cerveau et Vision, I.N.S.E.R.M. U-371, Avenue Doyen Lepine, 69500 Bron, France §Departm...
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