4.4 Article

Rab35 GTPase positively regulates endocytic recycling of cardiac KATP channels

Journal

CHANNELS
Volume 16, Issue 1, Pages 137-147

Publisher

TAYLOR & FRANCIS INC
DOI: 10.1080/19336950.2022.2090667

Keywords

K-ATP channel; Rab35; endocytic recycling; surface density; cardiomyocytes

Funding

  1. Soochow University
  2. High Level Personnel Project of Jiangsu Province [JCSSBS20210696]

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This study identified Rab35 GTPase as a key regulator of K-ATP channel endocytic recycling, which affects the surface expression and function of the channel. This finding provides a potential pharmacologic target for treating diseases associated with K-ATP channel trafficking defects.
ATP-sensitive K+ (K-ATP) channel couples membrane excitability to intracellular energy metabolism. Maintaining K-ATP channel surface expression is key to normal insulin secretion, blood pressure and cardioprotection. However, the molecular mechanisms regulating K-ATP channel internalization and endocytic recycling, which directly affect the surface expression of K-ATP channels, are poorly understood. Here we used the cardiac K-ATP channel subtype, Kir6.2/SUR2A, and characterized Rab35 GTPase as a key regulator of K-ATP channel endocytic recycling. Electrophysiological recordings and surface biotinylation assays showed decreased K-ATP channel surface density with co-expression of a dominant negative Rab35 mutant (Rab35-DN), but not other recycling-related Rab GTPases, including Rab4, Rab11a and Rab11b. Immunofluorescence images revealed strong colocalization of Rab35-DN with recycling Kir6.2. Rab35-DN minimized the recycling rate of K-ATP channels. Rab35 also regulated K-ATP channel current amplitude in isolated adult cardiomyocytes by affecting its surface expression but not channel properties, which validated its physiologic relevance and the potential of pharmacologic target for treating the diseases with K-ATP channel trafficking defects.

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