Dataset Information

The molecular nature of the 17β-Estradiol binding site in the voltage- and Ca²⁺-activated K⁺ (BK) channel β1 subunit.

ABSTRACT: The accessory β1 subunit modulates the Ca²⁺- and voltage-activated K⁺ (BK) channel gating properties mainly by increasing its apparent Ca²⁺ sensitivity. β1 plays an important role in the modulation of arterial tone and blood pressure by vascular smooth muscle cells (SMCs). 17β-estradiol (E2) increases the BK channel open probability (P_o) in SMCs, through a β1 subunit-dependent modulatory effect. Here, using molecular modeling, bioinformatics, mutagenesis, and electrophysiology, we identify a cluster of hydrophobic residues in the second transmembrane domain of the β1 subunit, including the residues W163 and F166, as the binding site for E2. We further show that the increase in P_o induced by E2 is associated with a stabilization of the voltage sensor in its active configuration and an increase in the coupling between the voltage sensor activation and pore opening. Since β1 is a key molecular player in vasoregulation, the findings reported here are of importance in the design of novel drugs able to modulate BK channels.

SUBMITTER: Granados ST

PROVIDER: S-EPMC6620312 | biostudies-literature | 2019 Jul

REPOSITORIES: biostudies-literature

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Publications

The molecular nature of the 17β-Estradiol binding site in the voltage- and Ca2+-activated K+ (BK) channel β1 subunit.

Granados Sara T ST Castillo Karen K Bravo-Moraga Felipe F Sepúlveda Romina V RV Carrasquel-Ursulaez Willy W Rojas Maximiliano M Carmona Emerson E Lorenzo-Ceballos Yenisleidy Y González-Nilo Fernando F González Carlos C Latorre Ramón R Torres Yolima P YP

Scientific reports 20190710 1

The accessory β1 subunit modulates the Ca2+- and voltage-activated K+ (BK) channel gating properties mainly by increasing its apparent Ca2+ sensitivity. β1 plays an important role in the modulation of arterial tone and blood pressure by vascular smooth muscle cells (SMCs). 17β-estradiol (E2) increases the BK channel open probability (Po) in SMCs, through a β1 subunit-dependent modulatory effect. Here, using molecular modeling, bioinformatics, mutagenes ...[more]

PMID: 31292456

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Project description:BackgroundVascular smooth muscle cells (VSMCs) phenotype switching is very important during the pathogenesis and progression of vascular diseases. However, it is not well understood how normal VSMCs maintain the differentiated state. The large-conductance Ca2+-activated K+ (BKCa) channels are widely expressed in VSMCs and regulate vascular tone. Nevertheless, there is limited understanding of the role of the BKCa channel in modulation of the VSMC phenotype.Methods and resultsWe assessed BKCa channel expression levels in normal and injured carotid arteries from rats of the balloon-injury model. A strong decrease of BKCa-β1 was seen in the injured carotid arteries, accompanied by a parallel decrease of the VSMC contractile markers. BKCa-β1 in primary rat aortic VSMCs was decreased with the increase of passage numbers and the stimulation of platelet-derived growth factor (PDGF)-BB. Conversely, transforming growth factor β upregulated BKCa-β1. Meanwhile, the BKCa-β1 level was positively associated with the levels of VSMC contractile proteins. Intravenous injection of PDGF-BB induced downregulation of BKCa-β1 expression in the carotid arteries. Knockdown of BKCa-β1 favored VSMC dedifferentiation, characterized by altered morphology, abnormal actin fiber organization, decreased contractile proteins expression and reduced contractile ability. Furthermore, the resultant VSMC dedifferentiated phenotype rendered increased proliferation, migration, enhanced inflammatory factors levels, and matrix metalloproteinases activity. Studies using primary cultured aortic VSMCs from human recapitulated key findings. Finally, protein level of BKCa-β1 was reduced in human atherosclerotic arteries.ConclusionBKCa-β1 is important in the maintenance of the contractile phenotype of VSMCs. As a novel endogenous defender that prevents pathological VSMC phenotype switching, BKCa-β1 may serve as a potential therapeutic target for treating vascular diseases including post-injury restenosis and atherosclerosis.

Dataset Information

The molecular nature of the 17β-Estradiol binding site in the voltage- and Ca²⁺-activated K⁺ (BK) channel β1 subunit.

Publications

The molecular nature of the 17β-Estradiol binding site in the voltage- and Ca<sup>2+</sup>-activated K<sup>+</sup> (BK) channel β1 subunit.

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