Inwardly rectifying potassium (Kir) channels are broadly expressed in both excitable and nonexcitable tissues, where they contribute to a wide variety of cellular functions. Numerous studies have established that rectification of Kir channels is not an inherent property of the channel protein itself, but rather reflects strong voltage dependence of channel block by intracellular cations, such as polyamines and Mg2+. Here, we identify a previously unknown mechanism of inward rectification in Kir4.1/Kir5.1 channels in the absence of these endogenous blockers. This novel intrinsic rectification originates from the voltage-dependent behavior of Kir4.1/Kir5.1, which is generated by the flux of potassium ions through the channel pore; the inward K+-flux induces the opening of the gate, whereas the outward flux is unable to maintain the gate open. This gating mechanism powered by the K+-flux is convergent with the gating of PIP2 because, at a saturating concentration, PIP2 greatly reduces the inward rectification. Our findings provide evidence of the coexistence of two rectification mechanisms in Kir4.1/Kir5.1 channels: the classical inward rectification induced by blocking cations and an intrinsic voltage-dependent mechanism generated by the K+-flux gating.
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April 05 2021
Kir4.1/Kir5.1 channels possess strong intrinsic inward rectification determined by a voltage-dependent K+-flux gating mechanism
Leticia G. Marmolejo-Murillo
,
1
Departamento de Medicina y Nutrición, División de Ciencias de la Salud, Universidad de Guanajuato, León, México
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Iván A. Aréchiga-Figueroa
,
2
Consejo Nacional de Ciencia y Tecnologia, Facultad de Medicina, Universidad Autónoma de San Luis Potosí, San Luis Potosí, México
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Eloy G. Moreno-Galindo
,
Eloy G. Moreno-Galindo
3
Centro Universitario de Investigaciones Biomédicas, Universidad de Colima, Colima, México
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Tania Ferrer
,
Tania Ferrer
3
Centro Universitario de Investigaciones Biomédicas, Universidad de Colima, Colima, México
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Rodrigo Zamora-Cárdenas
,
Rodrigo Zamora-Cárdenas
3
Centro Universitario de Investigaciones Biomédicas, Universidad de Colima, Colima, México
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Ricardo A. Navarro-Polanco
,
Ricardo A. Navarro-Polanco
3
Centro Universitario de Investigaciones Biomédicas, Universidad de Colima, Colima, México
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José A. Sánchez-Chapula
,
3
Centro Universitario de Investigaciones Biomédicas, Universidad de Colima, Colima, México
Correspondence to José A. Sánchez-Chapula: sancheza@ucol.mx
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Aldo A. Rodríguez-Menchaca
3
Centro Universitario de Investigaciones Biomédicas, Universidad de Colima, Colima, México
4
Departamento de Fisiología y Biofísica, Facultad de Medicina, Universidad Autónoma de San Luis Potosí, San Luis Potosí, México
Aldo A. Rodríguez-Menchaca: aldo.rodriguez@uaslp.mx
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Leticia G. Marmolejo-Murillo
1
Departamento de Medicina y Nutrición, División de Ciencias de la Salud, Universidad de Guanajuato, León, México
Iván A. Aréchiga-Figueroa
2
Consejo Nacional de Ciencia y Tecnologia, Facultad de Medicina, Universidad Autónoma de San Luis Potosí, San Luis Potosí, México
Eloy G. Moreno-Galindo
3
Centro Universitario de Investigaciones Biomédicas, Universidad de Colima, Colima, México
Tania Ferrer
3
Centro Universitario de Investigaciones Biomédicas, Universidad de Colima, Colima, México
Rodrigo Zamora-Cárdenas
3
Centro Universitario de Investigaciones Biomédicas, Universidad de Colima, Colima, México
Ricardo A. Navarro-Polanco
3
Centro Universitario de Investigaciones Biomédicas, Universidad de Colima, Colima, México
José A. Sánchez-Chapula
3
Centro Universitario de Investigaciones Biomédicas, Universidad de Colima, Colima, México
Aldo A. Rodríguez-Menchaca
3
Centro Universitario de Investigaciones Biomédicas, Universidad de Colima, Colima, México
4
Departamento de Fisiología y Biofísica, Facultad de Medicina, Universidad Autónoma de San Luis Potosí, San Luis Potosí, México
Correspondence to José A. Sánchez-Chapula: sancheza@ucol.mx
Aldo A. Rodríguez-Menchaca: aldo.rodriguez@uaslp.mx
*
L.G. Marmolejo-Murillo and I.A. Aréchiga-Figueroa contributed equally to this paper.
Received:
November 21 2019
Revision Received:
November 10 2020
Accepted:
March 16 2021
Online Issn: 1540-7748
Print Issn: 0022-1295
Funding:
Consejo Nacional de Ciencia y Tecnología
(NO AWARD, CB-2013-01-220546, CB-2016-01-284443)
© 2021 Marmolejo-Murillo et al.
2021
This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.rupress.org/terms/). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 4.0 International license, as described at https://creativecommons.org/licenses/by-nc-sa/4.0/).
J Gen Physiol (2021) 153 (5): e201912540.
Article history
Received:
November 21 2019
Revision Received:
November 10 2020
Accepted:
March 16 2021
Citation
Leticia G. Marmolejo-Murillo, Iván A. Aréchiga-Figueroa, Eloy G. Moreno-Galindo, Tania Ferrer, Rodrigo Zamora-Cárdenas, Ricardo A. Navarro-Polanco, José A. Sánchez-Chapula, Aldo A. Rodríguez-Menchaca; Kir4.1/Kir5.1 channels possess strong intrinsic inward rectification determined by a voltage-dependent K+-flux gating mechanism. J Gen Physiol 3 May 2021; 153 (5): e201912540. doi: https://doi.org/10.1085/jgp.201912540
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