更新于：2024-11-01

VDCCs x BACE

更新于：2024-11-01

基本信息

关联

项与 VDCCs x BACE 相关的药物

ARC-050

靶点

BACE x VDCCs

作用机制

BACE抑制剂 [+1]

在研机构-

原研机构

Archer Ltd.

在研适应症-

非在研适应症

阿尔茨海默症

最高研发阶段无进展

首次获批国家/地区-

首次获批日期1800-01-20

100 项与 VDCCs x BACE 相关的临床结果

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100 项与 VDCCs x BACE 相关的转化医学

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0 项与 VDCCs x BACE 相关的专利（医药）

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项与 VDCCs x BACE 相关的文献（医药）

2007-06-01·Nature Neuroscience1区 · 医学

RIM1 confers sustained activity and neurotransmitter vesicle anchoring to presynaptic Ca2+ channels

1区 · 医学

Article

作者: Motoi Kanagawa ; Takafumi Miki ; Shigeki Kiyonaka ; Yuji Hara ; Minoru Wakamori ; Aaron M Beedle ; Kevin P Campbell ; Emiko Mori ; Michel De Waard ; Mio Nonaka ; Yoshitsugu Uriu ; Makoto Itakura ; Yasuo Mori ; Masami Takahashi ; Haruhiko Bito

The molecular organization of presynaptic active zones is important for the neurotransmitter release that is triggered by depolarization-induced Ca2+ influx. Here, we demonstrate a previously unknown interaction between two components of the presynaptic active zone, RIM1 and voltage-dependent Ca2+ channels (VDCCs), that controls neurotransmitter release in mammalian neurons. RIM1 associated with VDCC beta-subunits via its C terminus to markedly suppress voltage-dependent inactivation among different neuronal VDCCs. Consistently, in pheochromocytoma neuroendocrine PC12 cells, acetylcholine release was significantly potentiated by the full-length and C-terminal RIM1 constructs, but membrane docking of vesicles was enhanced only by the full-length RIM1. The beta construct beta-AID dominant negative, which disrupts the RIM1-beta association, accelerated the inactivation of native VDCC currents, suppressed vesicle docking and acetylcholine release in PC12 cells, and inhibited glutamate release in cultured cerebellar neurons. Thus, RIM1 association with beta in the presynaptic active zone supports release via two distinct mechanisms: sustaining Ca2+ influx through inhibition of channel inactivation, and anchoring neurotransmitter-containing vesicles in the vicinity of VDCCs.

Frontiers in Physiology2区 · 医学

Partial Mechanical Unloading of the Heart Disrupts L-Type Calcium Channel and Beta-Adrenoceptor Signaling Microdomains

2区 · 医学

ArticleOA

作者: Faggian, Giuseppe ; Lucarelli, Carla ; Bello, Sean O ; Sanchez-Alonso, Jose L ; Wright, Peter T ; Gorelik, Julia ; Alvarez-Laviada, Anita ; Poulet, Claire E ; Terracciano, Cesare M

Introduction: We investigated the effect of partial mechanical unloading (PMU) of the heart on the physiology of calcium and beta-adrenoceptor-cAMP (βAR-cAMP) microdomains. Previous studies have investigated PMU using a model of heterotopic-heart and lung transplantation (HTHAL). These studies have demonstrated that PMU disrupts the structure of cardiomyocytes and calcium handling. We sought to understand these processes by studying L-Type Calcium Channel (LTCC) activity and sub-type-specific βAR-cAMP signaling within cardiomyocyte membrane microdomains. Method: We utilized an 8-week model of HTHAL, whereby the hearts of syngeneic Lewis rats were transplanted into the abdomens of randomly assigned cage mates. A pronounced atrophy was observed in hearts after HTHAL. Cardiomyocytes were isolated via enzymatic perfusion. We utilized Förster Resonance Energy Transfer (FRET) based cAMP-biosensors and scanning ion conductance microscopy (SICM) based methodologies to study localization of LTCC and βAR-cAMP signaling. Results: β₂AR-cAMP responses measured by FRET in the cardiomyocyte cytosol were reduced by PMU (loaded 28.51 ± 7.18% vs. unloaded 10.84 ± 3.27% N,n 4/10-13 mean ± SEM ^∗ p < 0.05). There was no effect of PMU on β₂AR-cAMP signaling in RII_Protein Kinase A domains. β₁AR-cAMP was unaffected by PMU in either microdomain. Consistent with this SICM/FRET analysis demonstrated that β₂AR-cAMP was specifically reduced in t-tubules (TTs) after PMU (loaded TT 0.721 ± 0.106% vs. loaded crest 0.104 ± 0.062%, unloaded TT 0.112 ± 0.072% vs. unloaded crest 0.219 ± 0.084% N,n 5/6-9 mean ± SEM ^∗∗ p < 0.01, ^∗∗∗ p < 0.001 vs. loaded TT). By comparison β₁AR-cAMP responses in either TT or sarcolemmal crests were unaffected by the PMU. LTCC occurrence and open probability (P_o) were reduced by PMU (loaded TT P_o 0.073 ± 0.011% vs. loaded crest P_o 0.027 ± 0.006% N,n 5/18-26 mean ± SEM ^∗ p < 0.05) (unloaded TT 0.0350 ± 0.003% vs. unloaded crest P_o 0.025 N,n 5/20-30 mean ± SEM NS ^# p < 0.05 unloaded vs. loaded TT). We discovered that PMU had reduced the association between Caveolin-3, Junctophilin-2, and Cav1.2. Discussion: PMU suppresses' β₂AR-cAMP and LTCC activity. When activated, the signaling of β₂AR-cAMP and LTCC become more far-reaching after PMU. We suggest that a situation of 'suppression/decompartmentation' is elicited by the loss of refined cardiomyocyte structure following PMU. As PMU is a component of modern device therapy for heart failure this study has clinical ramifications and raises important questions for regenerative medicine.