Please use this identifier to cite or link to this item: https://doi.org/10.1161/HYPERTENSIONAHA.122.19103
Title: S-Nitrosylation-Mediated Reduction of Ca(V)1.2 Surface Expression and Open Probability Underlies Attenuated Vasoconstriction Induced by Nitric Oxide
Authors: Hu, Zhenyu 
Zhang, Bo
Lim, Leon Jian Ying
Loh, Wei Zhern Kelvin 
Yu, Dejie 
Tan, Bryce Wei Quan 
Liang, Mui Cheng 
Huang, Zhongwei 
Leo, Chen Huei
Huang, Hua 
Soong, Tuck Wah 
Keywords: Science & Technology
Life Sciences & Biomedicine
Peripheral Vascular Disease
Cardiovascular System & Cardiology
Ca(V)1
2 channel
hypertension
lysosome
open probability
S-nitrosylation
SOLUBLE GUANYLATE-CYCLASE
CALCIUM-CHANNELS
ANGIOTENSIN-II
PROTEIN-KINASE
IN-VITRO
INHIBITION
CONTRACTION
RELAXATION
MECHANISM
Issue Date: 1-Dec-2022
Publisher: LIPPINCOTT WILLIAMS & WILKINS
Citation: Hu, Zhenyu, Zhang, Bo, Lim, Leon Jian Ying, Loh, Wei Zhern Kelvin, Yu, Dejie, Tan, Bryce Wei Quan, Liang, Mui Cheng, Huang, Zhongwei, Leo, Chen Huei, Huang, Hua, Soong, Tuck Wah (2022-12-01). S-Nitrosylation-Mediated Reduction of Ca(V)1.2 Surface Expression and Open Probability Underlies Attenuated Vasoconstriction Induced by Nitric Oxide. HYPERTENSION 79 (12) : 2854-2866. ScholarBank@NUS Repository. https://doi.org/10.1161/HYPERTENSIONAHA.122.19103
Abstract: Background: L-type CaV1.2 calcium channel, the primary gateway for Ca2+ influx in smooth muscles, is widely regulated by multiple posttranslational modifications, such as protein kinase-mediated phosphorylation and nitric oxide-induced S-nitrosylation. However, the effect of S-nitrosylation on CaV1.2 channel function and its role in arterial contractility are not well understood. Methods: Electrophysiological recordings, Ca2+ and confocal imaging, and biochemical assays were used to functionally characterize S-nitrosylated CaV1.2 channels in vitro, while pressure myography and tail-cuff blood pressure measurement were conducted to evaluate the physiological effects of CaV1.2 S-nitrosylation ex vivo and in vivo. Results: S-nitrosylation significantly reduced the CaV1.2 current density by promoting lysosomal degradation that leads to decreased levels of total and surface CaV1.2 channel proteins in a CaVβ-independent manner and reducing the open probability of CaV1.2 channel. Mechanistically, the Cys1180 and Cys1280 residues within CaV1.2 channel have been determined as the molecular targets for S-nitrosylation as substitution of either Cys1180 or Cys1280 for serine resulted in substantial reduction of S-nitrosylation levels. Of note, CaV1.2 S-nitrosylation levels were significantly reduced in arteries isolated from both spontaneously hypertensive rats and patients with pulmonary hypertension. Moreover, mouse resistance arteries incubated with S-nitrosocysteine displayed much lower contractility and spontaneously hypertensive rats injected with S-nitrosocysteine also showed significantly reduced blood pressure, suggesting that reduced S-nitrosylation contributes to the upregulation of CaV1.2 channel activity in hypertensive arteries. Conclusions: This study provides strong evidence that S-nitrosylation-mediated downregulation of CaV1.2 channels is via 2 distinctive mechanisms and the findings offer potential pathways for therapeutic inventions in hypertension.
Source Title: HYPERTENSION
URI: https://scholarbank.nus.edu.sg/handle/10635/237717
ISSN: 0194-911X
1524-4563
DOI: 10.1161/HYPERTENSIONAHA.122.19103
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