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Characterization of hyperactive mutations in the renal potassium channel ROMK uncovers unique effects on channel biogenesis and ion conductance.
Nguyen, Nga H; Sheng, Shaohu; Banerjee, Anupam; Guerriero, Christopher J; Chen, Jingxin; Wang, Xueqi; Mackie, Timothy D; Welling, Paul A; Kleyman, Thomas R; Bahar, Ivet; Carlson, Anne E; Brodsky, Jeffrey L.
Afiliación
  • Nguyen NH; Department of Biological Sciences, School of Medicine, University of Pittsburgh, PA 15260.
  • Sheng S; Renal-Electrolyte Division, Department of Medicine, School of Medicine, University of Pittsburgh, PA 15260.
  • Banerjee A; Department of Computational and Systems Biology, School of Medicine, University of Pittsburgh, PA 15260.
  • Guerriero CJ; Department of Biological Sciences, School of Medicine, University of Pittsburgh, PA 15260.
  • Chen J; Renal-Electrolyte Division, Department of Medicine, School of Medicine, University of Pittsburgh, PA 15260.
  • Wang X; Renal-Electrolyte Division, Department of Medicine, School of Medicine, University of Pittsburgh, PA 15260.
  • Mackie TD; Department of Biological Sciences, School of Medicine, University of Pittsburgh, PA 15260.
  • Welling PA; Division of Nephrology, Department of Medicine, Johns Hopkins School of Medicine, Baltimore, MD 21205.
  • Kleyman TR; Renal-Electrolyte Division, Department of Medicine, School of Medicine, University of Pittsburgh, PA 15260.
  • Bahar I; Department of Computational and Systems Biology, School of Medicine, University of Pittsburgh, PA 15260.
  • Carlson AE; Department of Biological Sciences, School of Medicine, University of Pittsburgh, PA 15260.
  • Brodsky JL; Department of Biological Sciences, School of Medicine, University of Pittsburgh, PA 15260.
Mol Biol Cell ; 35(9): ar119, 2024 Sep 01.
Article en En | MEDLINE | ID: mdl-39024255
ABSTRACT
Hypertension affects one billion people worldwide and is the most common risk factor for cardiovascular disease, yet a comprehensive picture of its underlying genetic factors is incomplete. Amongst regulators of blood pressure is the renal outer medullary potassium (ROMK) channel. While select ROMK mutants are prone to premature degradation and lead to disease, heterozygous carriers of some of these same alleles are protected from hypertension. Therefore, we hypothesized that gain-of-function (GoF) ROMK variants which increase potassium flux may predispose people to hypertension. To begin to test this hypothesis, we employed genetic screens and a candidate-based approach to identify six GoF variants in yeast. Subsequent functional assays in higher cells revealed two variant classes. The first group exhibited greater stability in the endoplasmic reticulum, enhanced channel assembly, and/or increased protein at the cell surface. The second group of variants resided in the PIP2-binding pocket, and computational modeling coupled with patch-clamp studies demonstrated lower free energy for channel opening and slowed current rundown, consistent with an acquired PIP2-activated state. Together, these findings advance our understanding of ROMK structure-function, suggest the existence of hyperactive ROMK alleles in humans, and establish a system to facilitate the development of ROMK-targeted antihypertensives.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Canales de Potasio de Rectificación Interna Límite: Humans Idioma: En Revista: Mol Biol Cell Asunto de la revista: BIOLOGIA MOLECULAR Año: 2024 Tipo del documento: Article Pais de publicación: Estados Unidos
Texto completo
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XML
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Canales de Potasio de Rectificación Interna Límite: Humans Idioma: En Revista: Mol Biol Cell Asunto de la revista: BIOLOGIA MOLECULAR Año: 2024 Tipo del documento: Article Pais de publicación: Estados Unidos