Assembly of distinct α subunits of Kv1 (voltage-gated K+ channels) into tetramers underlies the diversity of their outward currents in neurons. Kv1.4-containing channels normally exhibit N-type rapid inactivation, mediated through an NIB (N-terminal inactivation ball); this can be over-ridden if associated with a Kv1.6 α subunit, via its NIP (N-type inactivation prevention) domain. Herein, NIP function was shown to require positioning of Kv1.6 adjacent to the Kv1.4 subunit. Using a recently devised gene concatenation, heterotetrameric Kv1 channels were expressed as single-chain proteins on the plasmalemma of HEK (human embryonic kidney)-293 cells, so their constituents could be arranged in different positions. Placing the Kv1.4 and 1.6 genes together, followed by two copies of Kv1.2, yielded a K+ current devoid of fast inactivation. Mutation of critical glutamates within the NIP endowed rapid inactivation. Moreover, separating Kv1.4 and 1.6 with a copy of Kv1.2 gave a fast-inactivating K+ current with steady-state inactivation shifted to more negative potentials and exhibiting slower recovery, correlating with similar inactivation kinetics seen for Kv1.4-(1.2)3. Alternatively, separating Kv1.4 and 1.6 with two copies of Kv1.2 yielded slow-inactivating currents, because in this concatamer Kv1.4 and 1.6 should be together. These findings also confirm that the gene concatenation can generate K+ channels with α subunits in pre-determined positions.
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Research Article|
August 12 2011
Position-dependent attenuation by Kv1.6 of N-type inactivation of Kv1.4-containing channels
Ahmed Al-Sabi;
Ahmed Al-Sabi
1International Centre for Neurotherapeutics, Dublin City University, Glasnevin, Dublin 9, Ireland
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Seshu Kaza;
Seshu Kaza
1International Centre for Neurotherapeutics, Dublin City University, Glasnevin, Dublin 9, Ireland
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Marie Le Berre;
Marie Le Berre
1International Centre for Neurotherapeutics, Dublin City University, Glasnevin, Dublin 9, Ireland
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Liam O'Hara;
Liam O'Hara
1International Centre for Neurotherapeutics, Dublin City University, Glasnevin, Dublin 9, Ireland
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MacDara Bodeker;
MacDara Bodeker
1International Centre for Neurotherapeutics, Dublin City University, Glasnevin, Dublin 9, Ireland
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Jiafu Wang;
Jiafu Wang
1International Centre for Neurotherapeutics, Dublin City University, Glasnevin, Dublin 9, Ireland
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J. Oliver Dolly
J. Oliver Dolly
1
1International Centre for Neurotherapeutics, Dublin City University, Glasnevin, Dublin 9, Ireland
1To whom correspondence should be addressed (e-mail oliver.dolly@dcu.ie).
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Publisher: Portland Press Ltd
Received:
January 04 2011
Revision Received:
February 21 2011
Accepted:
July 15 2011
Accepted Manuscript online:
July 15 2011
Online ISSN: 1470-8728
Print ISSN: 0264-6021
© The Authors Journal compilation © 2011 Biochemical Society
2011
Biochem J (2011) 438 (2): 389–396.
Article history
Received:
January 04 2011
Revision Received:
February 21 2011
Accepted:
July 15 2011
Accepted Manuscript online:
July 15 2011
Citation
Ahmed Al-Sabi, Seshu Kaza, Marie Le Berre, Liam O'Hara, MacDara Bodeker, Jiafu Wang, J. Oliver Dolly; Position-dependent attenuation by Kv1.6 of N-type inactivation of Kv1.4-containing channels. Biochem J 1 September 2011; 438 (2): 389–396. doi: https://doi.org/10.1042/BJ20102169
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