TY - JOUR
T1 - The molecular nature of the 17β-Estradiol binding site in the voltage- and Ca2+-activated K+ (BK) channel β1 subunit
AU - Granados, Sara T.
AU - Castillo, Karen
AU - Bravo-Moraga, Felipe
AU - Sepúlveda, Romina V.
AU - Carrasquel-Ursulaez, Willy
AU - Rojas, Maximiliano
AU - Carmona, Emerson
AU - Lorenzo-Ceballos, Yenisleidy
AU - González-Nilo, Fernando
AU - González, Carlos
AU - Latorre, Ramón
AU - Torres, Yolima P.
N1 - Funding Information:
We would like to thank Miss Luisa Soto and Mrs Victoria Devia for their excellent technical assistance and Dr Alfonso Barreto for his helpful comments regarding the confocal assays. We also thank Drs. Miguel A. Valverde and Jose M. Fernandez for comments on an early version of the manuscript. This work was supported by Projects FONDECYT 1150273 and 1190203 (to R. Latorre), 1180464 (to C. Gonzalez), 1180999 (to K.Castillo) and 1131003 (to F. Gonzalez-Nilo) and by COLCIENCIAS Grant ID 120352128651 (YP Torres), COLCIENCIAS PhD Scholarship 528 (to ST. Granados) and Air Force Office of Scientific Research grant under award number FA9550-16-1-0384 (R. Latorre). The Centro Interdisciplinario de Neurociencia de Valparaíso is a Millennium Institute supported by the Millennium Scientific Initiative of the Ministerio de Economía, Fomento y Turismo.
Publisher Copyright:
© 2019, The Author(s).
PY - 2019/12/1
Y1 - 2019/12/1
N2 - 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, 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 Po 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.
AB - 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, 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 Po 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.
UR - http://www.scopus.com/inward/record.url?scp=85068895182&partnerID=8YFLogxK
U2 - 10.1038/s41598-019-45942-1
DO - 10.1038/s41598-019-45942-1
M3 - Article
AN - SCOPUS:85068895182
SN - 2045-2322
VL - 9
JO - Scientific Reports
JF - Scientific Reports
IS - 1
M1 - 9965
ER -