Sigma-1 receptor modulation fine-tunes KV1.5 channels and impacts pulmonary vascular function
KV1.5 channels are key players in the regulation of vascular tone and atrial excitability and their impairment is associated with cardiovascular diseases including pulmonary arterial hypertension (PAH) and atrial fibrillation (AF). Unfortunately, pharmacological strategies to improve KV1.5 channel f...
| Main Authors: | , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Elsevier
2023-03-01
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| Series: | Pharmacological Research |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S1043661823000403 |
| _version_ | 1797448119413112832 |
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| author | Alba Vera-Zambrano Maria Baena-Nuevo Susanne Rinné Marta Villegas-Esguevillas Bianca Barreira Gokcen Telli Angela de Benito-Bueno José Antonio Blázquez Belén Climent Francisco Pérez-Vizcaino Carmen Valenzuela Niels Decher Teresa Gonzalez Angel Cogolludo |
| author_facet | Alba Vera-Zambrano Maria Baena-Nuevo Susanne Rinné Marta Villegas-Esguevillas Bianca Barreira Gokcen Telli Angela de Benito-Bueno José Antonio Blázquez Belén Climent Francisco Pérez-Vizcaino Carmen Valenzuela Niels Decher Teresa Gonzalez Angel Cogolludo |
| author_sort | Alba Vera-Zambrano |
| collection | DOAJ |
| description | KV1.5 channels are key players in the regulation of vascular tone and atrial excitability and their impairment is associated with cardiovascular diseases including pulmonary arterial hypertension (PAH) and atrial fibrillation (AF). Unfortunately, pharmacological strategies to improve KV1.5 channel function are missing. Herein, we aimed to study whether the chaperone sigma-1 receptor (S1R) is able to regulate these channels and represent a new strategy to enhance their function. By using different electrophysiological and molecular techniques in X. laevis oocytes and HEK293 cells, we demonstrate that S1R physically interacts with KV1.5 channels and regulate their expression and function. S1R induced a bimodal regulation of KV1.5 channel expression/activity, increasing it at low concentrations and decreasing it at high concentrations. Of note, S1R agonists (PRE084 and SKF10047) increased, whereas the S1R antagonist BD1047 decreased, KV1.5 expression and activity. Moreover, PRE084 markedly increased KV1.5 currents in pulmonary artery smooth muscle cells and attenuated vasoconstriction and proliferation in pulmonary arteries. We also show that both KV1.5 channels and S1R, at mRNA and protein levels, are clearly downregulated in samples from PAH and AF patients. Moreover, the expression of both genes showed a positive correlation. Finally, the ability of PRE084 to increase KV1.5 function was preserved under sustained hypoxic conditions, as an in vitro PAH model. Our study provides insight into the key role of S1R in modulating the expression and activity of KV1.5 channels and highlights the potential role of this chaperone as a novel pharmacological target for pathological conditions associated with KV1.5 channel dysfunction. |
| first_indexed | 2024-03-09T14:05:51Z |
| format | Article |
| id | doaj.art-669cefd33c57474f939a3f93d47c212f |
| institution | Directory Open Access Journal |
| issn | 1096-1186 |
| language | English |
| last_indexed | 2024-03-09T14:05:51Z |
| publishDate | 2023-03-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Pharmacological Research |
| spelling | doaj.art-669cefd33c57474f939a3f93d47c212f2023-11-30T05:05:44ZengElsevierPharmacological Research1096-11862023-03-01189106684Sigma-1 receptor modulation fine-tunes KV1.5 channels and impacts pulmonary vascular functionAlba Vera-Zambrano0Maria Baena-Nuevo1Susanne Rinné2Marta Villegas-Esguevillas3Bianca Barreira4Gokcen Telli5Angela de Benito-Bueno6José Antonio Blázquez7Belén Climent8Francisco Pérez-Vizcaino9Carmen Valenzuela10Niels Decher11Teresa Gonzalez12Angel Cogolludo13Department of Biochemistry, School of Medicine, Universidad Autónoma de Madrid, Madrid, Spain; Instituto de Investigaciones Biomédicas “Alberto Sols” CSIC-UAM, Madrid, Spain; Department of Pharmacology and Toxicology, School of Medicine, University Complutense of Madrid, Madrid, Spain; Corresponding authors at: Department of Pharmacology and Toxicology, School of Medicine, University Complutense of Madrid, Ciudad Universitaria S/N, 28040 Madrid, Spain.Instituto de Investigaciones Biomédicas “Alberto Sols” CSIC-UAM, Madrid, SpainInstitute of Physiology and Pathophysiology, Vegetative Physiology, University of Marburg, 35043 Marburg, GermanyDepartment of Pharmacology and Toxicology, School of Medicine, University Complutense of Madrid, Madrid, Spain; Ciber Enfermedades Respiratorias (CIBERES), Spain; Instituto de Investigación Sanitaria Gregorio Marañón (IiSGM), Madrid, SpainDepartment of Pharmacology and Toxicology, School of Medicine, University Complutense of Madrid, Madrid, Spain; Ciber Enfermedades Respiratorias (CIBERES), Spain; Instituto de Investigación Sanitaria Gregorio Marañón (IiSGM), Madrid, SpainHacettepe University, Department of Pharmacology, Faculty of Pharmacy, Ankara, TurkeyInstituto de Investigaciones Biomédicas “Alberto Sols” CSIC-UAM, Madrid, SpainDepartamento de Cirugía Cardiaca, Hospital Universitario La Paz, Madrid, SpainDepartment of Physiology, Faculty of Pharmacy, University Complutense of Madrid, Madrid, SpainDepartment of Pharmacology and Toxicology, School of Medicine, University Complutense of Madrid, Madrid, Spain; Ciber Enfermedades Respiratorias (CIBERES), Spain; Instituto de Investigación Sanitaria Gregorio Marañón (IiSGM), Madrid, SpainInstituto de Investigaciones Biomédicas “Alberto Sols” CSIC-UAM, Madrid, Spain; Spanish Network for Biomedical Research in Cardiovascular Research (CIBERCV), Instituto de Salud Carlos III, Madrid, SpainInstitute of Physiology and Pathophysiology, Vegetative Physiology, University of Marburg, 35043 Marburg, GermanyDepartment of Biochemistry, School of Medicine, Universidad Autónoma de Madrid, Madrid, Spain; Instituto de Investigaciones Biomédicas “Alberto Sols” CSIC-UAM, Madrid, Spain; Department of Physiology, Faculty of Pharmacy, University Complutense of Madrid, Madrid, SpainDepartment of Pharmacology and Toxicology, School of Medicine, University Complutense of Madrid, Madrid, Spain; Ciber Enfermedades Respiratorias (CIBERES), Spain; Instituto de Investigación Sanitaria Gregorio Marañón (IiSGM), Madrid, Spain; Corresponding authors at: Department of Pharmacology and Toxicology, School of Medicine, University Complutense of Madrid, Ciudad Universitaria S/N, 28040 Madrid, Spain.KV1.5 channels are key players in the regulation of vascular tone and atrial excitability and their impairment is associated with cardiovascular diseases including pulmonary arterial hypertension (PAH) and atrial fibrillation (AF). Unfortunately, pharmacological strategies to improve KV1.5 channel function are missing. Herein, we aimed to study whether the chaperone sigma-1 receptor (S1R) is able to regulate these channels and represent a new strategy to enhance their function. By using different electrophysiological and molecular techniques in X. laevis oocytes and HEK293 cells, we demonstrate that S1R physically interacts with KV1.5 channels and regulate their expression and function. S1R induced a bimodal regulation of KV1.5 channel expression/activity, increasing it at low concentrations and decreasing it at high concentrations. Of note, S1R agonists (PRE084 and SKF10047) increased, whereas the S1R antagonist BD1047 decreased, KV1.5 expression and activity. Moreover, PRE084 markedly increased KV1.5 currents in pulmonary artery smooth muscle cells and attenuated vasoconstriction and proliferation in pulmonary arteries. We also show that both KV1.5 channels and S1R, at mRNA and protein levels, are clearly downregulated in samples from PAH and AF patients. Moreover, the expression of both genes showed a positive correlation. Finally, the ability of PRE084 to increase KV1.5 function was preserved under sustained hypoxic conditions, as an in vitro PAH model. Our study provides insight into the key role of S1R in modulating the expression and activity of KV1.5 channels and highlights the potential role of this chaperone as a novel pharmacological target for pathological conditions associated with KV1.5 channel dysfunction.http://www.sciencedirect.com/science/article/pii/S1043661823000403KV1.5 channelsSigma-1 receptorPulmonary arterial hypertensionS1R agonistsPotassium channel modulationAtrial fibrillation |
| spellingShingle | Alba Vera-Zambrano Maria Baena-Nuevo Susanne Rinné Marta Villegas-Esguevillas Bianca Barreira Gokcen Telli Angela de Benito-Bueno José Antonio Blázquez Belén Climent Francisco Pérez-Vizcaino Carmen Valenzuela Niels Decher Teresa Gonzalez Angel Cogolludo Sigma-1 receptor modulation fine-tunes KV1.5 channels and impacts pulmonary vascular function Pharmacological Research KV1.5 channels Sigma-1 receptor Pulmonary arterial hypertension S1R agonists Potassium channel modulation Atrial fibrillation |
| title | Sigma-1 receptor modulation fine-tunes KV1.5 channels and impacts pulmonary vascular function |
| title_full | Sigma-1 receptor modulation fine-tunes KV1.5 channels and impacts pulmonary vascular function |
| title_fullStr | Sigma-1 receptor modulation fine-tunes KV1.5 channels and impacts pulmonary vascular function |
| title_full_unstemmed | Sigma-1 receptor modulation fine-tunes KV1.5 channels and impacts pulmonary vascular function |
| title_short | Sigma-1 receptor modulation fine-tunes KV1.5 channels and impacts pulmonary vascular function |
| title_sort | sigma 1 receptor modulation fine tunes kv1 5 channels and impacts pulmonary vascular function |
| topic | KV1.5 channels Sigma-1 receptor Pulmonary arterial hypertension S1R agonists Potassium channel modulation Atrial fibrillation |
| url | http://www.sciencedirect.com/science/article/pii/S1043661823000403 |
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