Abstract
The cardiac mechanosensitive BK (Slo1) channels are gated by Ca2+, voltage, and membrane stretch. The neuropeptide GsMTx4 is a selective inhibitor of mechanosensitive (MS) channels. It has been reported to suppress stretch-induced cardiac fibrillation in the heart, but the mechanism underlying the specificity and even the targeting channel(s) in the heart remain elusive. Here, we report that GsMTx4 inhibits a stretch-activated BK channel (SAKcaC) in the heart through a modulation specific to mechano-gating. We show that membrane stretching increases while GsMTx4 decreases the open probability (Po) of SAKcaC. These effects were mostly abolished by the deletion of the STREX axis-regulated (STREX) exon located between RCK1 and RCK2 domains in BK channels. Single-channel kinetics analysis revealed that membrane stretch activates SAKcaC by prolonging the open-time duration (τO) and shortening the closed-time constant (τC). In contrast, GsMTx4 reversed the effects of membrane stretch, suggesting that GsMTx4 inhibits SAKcaC activity by interfering with mechano-gating of the channel. Moreover, GsMTx4 exerted stronger efficacy on SAKcaC under membrane-hyperpolarized/resting conditions. Molecular dynamics simulation study revealed that GsMTx4 appeared to have the ability to penetrate deeply within the bilayer, thus generating strong membrane deformation under the hyperpolarizing/resting conditions. Immunostaining results indicate that BK variants containing STREX are also expressed in mouse ventricular cardiomyocytes. Our results provide common mechanisms of peptide actions on MS channels and may give clues to therapeutic suppression of cardiac arrhythmias caused by excitatory currents through MS channels under hyper-mechanical stress in the heart.
Highlights
The cardiac mechanosensitive BK (Slo1) channels are gated by Ca2؉, voltage, and membrane stretch
Similar to our observations with other BK channels, in inside-out patch-clamp recordings from cultured ventricular myocytes isolated from the chick heart, we observed ongoing spontaneous activity of SAKcaC with a high concentration of Ca2ϩ in the intracellular side [26], and the channel activity did not inactivate or rundown during the recordings
The ion selectivity (Kϩ/Naϩ) and single channel conductance were not altered by GsMTx4 (Fig. S1, A and B), consistent with the idea that GsMTx4 acts as a gating modifier on MS channels
Summary
Hui Li‡1, Jie Xu‡1, Zhong-Shan Shen‡1, Guang-Ming Wang‡1, Mingxi Tang§, Xiang-Rong Du‡, Yan-Tian Lv‡, Jing-Jing Wang‡, Fei-Fei Zhang‡, Zhi Qi¶, Zhe Zhang‡, Masahiro Sokabeʈ**‡‡2, and X Qiong-Yao Tang‡ʈ3 From the ‡Jiangsu Province Key Laboratory of Anesthesiology, Xuzhou Medical University, Xuzhou, Jiangsu Province 221004, China, the §Department of Pathology, Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan Province 646000, China, the ¶Department of Basic Medical Sciences, Medical College of Xiamen University, Xiamen 361102, China, the ʈICORP Cell Mechanosensing, Japan Science and Technology Agency, Nagoya 466-8550, Japan, the **Mechanobiology Laboratory and ‡‡Department of Physiology, Nagoya University, Graduate School of Medicine, Nagoya 466-8550, Japan
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