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Structural bases of inhibitory mechanism of Ca_V1.2 channel inhibitors.

ABSTRACT: The voltage-gated calcium channel Ca_V1.2 is essential for cardiac and vessel smooth muscle contractility and brain function. Accumulating evidence demonstrates that malfunctions of Ca_V1.2 are involved in brain and heart diseases. Pharmacological inhibition of Ca_V1.2 is therefore of therapeutic value. Here, we report cryo-EM structures of Ca_V1.2 in the absence or presence of the antirheumatic drug tetrandrine or antihypertensive drug benidipine. Tetrandrine acts as a pore blocker in a pocket composed of S6^II, S6^III, and S6^IV helices and forms extensive hydrophobic interactions with Ca_V1.2. Our structure elucidates that benidipine is located in the D_III-D_IV fenestration site. Its hydrophobic sidechain, phenylpiperidine, is positioned at the exterior of the pore domain and cradled within a hydrophobic pocket formed by S5^DIII, S6^DIII, and S6^DIV helices, providing additional interactions to exert inhibitory effects on both L-type and T-type voltage gated calcium channels. These findings provide the structural foundation for the rational design and optimization of therapeutic inhibitors of voltage-gated calcium channels.

SUBMITTER: Wei Y

PROVIDER: S-EPMC10981686 | biostudies-literature | 2024 Mar

REPOSITORIES: biostudies-literature

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Structural bases of inhibitory mechanism of CaV1.2 channel inhibitors.

Wei Yiqing Y Yu Zhuoya Z Wang Lili L Li Xiaojing X Li Na N Bai Qinru Q Wang Yuhang Y Li Renjie R Meng Yufei Y Xu Hao H Wang Xianping X Dong Yanli Y Huang Zhuo Z Zhang Xuejun Cai XC Zhao Yan Y

Nature communications 20240330 1

The voltage-gated calcium channel CaV1.2 is essential for cardiac and vessel smooth muscle contractility and brain function. Accumulating evidence demonstrates that malfunctions of CaV1.2 are involved in brain and heart diseases. Pharmacological inhibition of CaV1.2 is therefore of therapeutic value. Here, we report cryo-EM structures of CaV1.2 in the absence or presence of the antirheumatic drug tetrandrine or antihypertensive drug benidipine. Tetrand ...[more]

PMID: 38555290

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Project description:BackgroundL-type Ca2+ channel CaV1.2 is essential for cardiomyocyte excitation, contraction and gene transcription in the heart, and abnormal functions of cardiac CaV1.2 channels are presented in diabetic cardiomyopathy. However, the underlying mechanisms are largely unclear. The functions of CaV1.2 channels are subtly modulated by splicing factor-mediated alternative splicing (AS), but whether and how CaV1.2 channels are alternatively spliced in diabetic heart remains unknown.MethodsDiabetic rat models were established by using high-fat diet in combination with low dose streptozotocin. Cardiac function and morphology were assessed by echocardiography and HE staining, respectively. Isolated neonatal rat ventricular myocytes (NRVMs) were used as a cell-based model. Cardiac CaV1.2 channel functions were measured by whole-cell patch clamp, and intracellular Ca2+ concentration was monitored by using Fluo-4 AM.ResultsWe find that diabetic rats develop diastolic dysfunction and cardiac hypertrophy accompanied by an increased CaV1.2 channel with alternative exon 9* (CaV1.2E9*), but unchanged that with alternative exon 8/8a or exon 33. The splicing factor Rbfox2 expression is also increased in diabetic heart, presumably because of dominate-negative (DN) isoform. Unexpectedly, high glucose cannot induce the aberrant expressions of CaV1.2 exon 9* and Rbfox2. But glycated serum (GS), the mimic of advanced glycation end-products (AGEs), upregulates CaV1.2E9* channels proportion and downregulates Rbfox2 expression in NRVMs. By whole-cell patch clamp, we find GS application hyperpolarizes the current-voltage curve and window currents of cardiac CaV1.2 channels. Moreover, GS treatment raises K+-triggered intracellular Ca2+ concentration ([Ca2+]i), enlarges cell surface area of NRVMs and induces hypertrophic genes transcription. Consistently, siRNA-mediated knockdown of Rbfox2 in NRVMs upregulates CaV1.2E9* channel, shifts CaV1.2 window currents to hyperpolarization, increases [Ca2+]i and induces cardiomyocyte hypertrophy.ConclusionsAGEs, not glucose, dysregulates Rbfox2 which thereby increases CaV1.2E9* channels and hyperpolarizes channel window currents. These make the channels open at greater negative potentials and lead to increased [Ca2+]i in cardiomyocytes, and finally induce cardiomyocyte hypertrophy in diabetes. Our work elucidates the underlying mechanisms for CaV1.2 channel regulation in diabetic heart, and targeting Rbfox2 to reset the aberrantly spliced CaV1.2 channel might be a promising therapeutic approach in diabetes-induced cardiac hypertrophy.

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Structural bases of inhibitory mechanism of Ca_V1.2 channel inhibitors.

Publications

Structural bases of inhibitory mechanism of Ca<sub>V</sub>1.2 channel inhibitors.

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