Activation of human smooth muscle BK channels by hydrochlorothiazide requires cell integrity and the presence of BK β1 subunit

Thiazide-like diuretics are the most commonly used drugs to treat arterial hypertension, with their efficacy being linked to their chronic vasodilatory effect. Previous studies suggest that activation of the large conductance voltage- and Ca2+-dependent K+ (BK) channel (Slo 1, MaxiK channel) is resp...

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Autores principales:	Martín, Pedro, Moncada, Melisa, Kuntamallappanavar, Guruprasad, Dopico, Alex M., Milesi, Verónica
Formato:	Articulo
Lenguaje:	Inglés
Publicado:	2018
Materias:	Biología Ciencias Médicas Thiazide Hydrochlorothiazide BK channel Slo1 β1-subunit Vascular smooth muscle cells Human umbilical artery Patchclamp electrophysiology
Acceso en línea:	http://sedici.unlp.edu.ar/handle/10915/107635 http://europepmc.org/backend/ptpmcrender.fcgi?accid=PMC5843832&blobtype=pdf
Aporte de:	SEDICI (UNLP) de Universidad Nacional de La Plata

id	I19-R120-10915-107635
record_format	dspace
institution	Universidad Nacional de La Plata
institution_str	I-19
repository_str	R-120
collection	SEDICI (UNLP)
language	Inglés
topic	Biología Ciencias Médicas Thiazide Hydrochlorothiazide BK channel Slo1 β1-subunit Vascular smooth muscle cells Human umbilical artery Patchclamp electrophysiology
spellingShingle	Biología Ciencias Médicas Thiazide Hydrochlorothiazide BK channel Slo1 β1-subunit Vascular smooth muscle cells Human umbilical artery Patchclamp electrophysiology Martín, Pedro Moncada, Melisa Kuntamallappanavar, Guruprasad Dopico, Alex M. Milesi, Verónica Activation of human smooth muscle BK channels by hydrochlorothiazide requires cell integrity and the presence of BK β1 subunit
topic_facet	Biología Ciencias Médicas Thiazide Hydrochlorothiazide BK channel Slo1 β1-subunit Vascular smooth muscle cells Human umbilical artery Patchclamp electrophysiology
description	Thiazide-like diuretics are the most commonly used drugs to treat arterial hypertension, with their efficacy being linked to their chronic vasodilatory effect. Previous studies suggest that activation of the large conductance voltage- and Ca2+-dependent K+ (BK) channel (Slo 1, MaxiK channel) is responsible for the thiazide-induced vasodilatory effect. But the direct electrophysiological evidence supporting this claim is lacking. BK channels can be associated with one small accessory β-subunit (β1–β4) that confers specific biophysical and pharmacological characteristics to the current phenotype. The β1-subunit is primarily expressed in smooth muscle cells (SMCs). In this study we investigated the effect of hydrochlorothiazide (HCTZ) on BK channel activity in native SMCs from human umbilical artery (HUASMCs) and HEK293T cells expressing the BK channel (with and without the β1-subunit). Bath application of HCTZ (10 µmol/L) significantly augmented the BK current in HUASMCs when recorded using the whole-cell configurations, but it did not affect the unitary conductance and open probability of the BK channel in HUASMCs evaluated in the inside-out configuration, suggesting an indirect mechanism requiring cell integrity. In HEK293T cells expressing BK channels, HCTZ-augmented BK channel activity was only observed when the β1-subunit was co-expressed, being concentration-dependent with an EC50 of 28.4 µmol/L, whereas membrane potential did not influence the concentration relationship. Moreover, HCTZ did not affect the BK channel current in HEK293T cells evaluated in the inside-out configuration, but significantly increases the open probability in the cell-attached configuration. Our data demonstrate that a β1-subunit-dependent mechanism that requires SMC integrity leads to HCTZ-induced BK channel activation.
format	Articulo Articulo
author	Martín, Pedro Moncada, Melisa Kuntamallappanavar, Guruprasad Dopico, Alex M. Milesi, Verónica
author_facet	Martín, Pedro Moncada, Melisa Kuntamallappanavar, Guruprasad Dopico, Alex M. Milesi, Verónica
author_sort	Martín, Pedro
title	Activation of human smooth muscle BK channels by hydrochlorothiazide requires cell integrity and the presence of BK β1 subunit
title_short	Activation of human smooth muscle BK channels by hydrochlorothiazide requires cell integrity and the presence of BK β1 subunit
title_full	Activation of human smooth muscle BK channels by hydrochlorothiazide requires cell integrity and the presence of BK β1 subunit
title_fullStr	Activation of human smooth muscle BK channels by hydrochlorothiazide requires cell integrity and the presence of BK β1 subunit
title_full_unstemmed	Activation of human smooth muscle BK channels by hydrochlorothiazide requires cell integrity and the presence of BK β1 subunit
title_sort	activation of human smooth muscle bk channels by hydrochlorothiazide requires cell integrity and the presence of bk β1 subunit
publishDate	2018
url	http://sedici.unlp.edu.ar/handle/10915/107635 http://europepmc.org/backend/ptpmcrender.fcgi?accid=PMC5843832&blobtype=pdf
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Activation of human smooth muscle BK channels by hydrochlorothiazide requires cell integrity and the presence of BK β1 subunit

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