Abstract：
TRPV2 voltage-insensitive, calcium-permeable ion channels play important roles in cancer progression, immune response, and neuronal development. Despite TRPV2\'s physiological impact, underlying endogenous proteins mediating TRPV2 responses and affected signaling pathways remain elusive. Using quantitative peroxidase-catalyzed (APEX2) proximity proteomics we uncover dynamic changes in the TRPV2-proximal proteome and identify calcium signaling and cell adhesion factors recruited to the molecular channel neighborhood in response to activation. Quantitative TRPV2 proximity proteomics further revealed activation-induced enrichment of protein clusters with biological functions in neural and cellular projection. We demonstrate a functional connection between TRPV2 and the neural immunoglobulin cell adhesion molecules NCAM and L1CAM. NCAM and L1CAM stimulation robustly induces TRPV2 [Ca2+]I flux in neuronal PC12 cells and this TRPV2-specific [Ca2+]I flux requires activation of the protein kinase PKCα. TRPV2 expression directly impacts neurite lengths that are modulated by NCAM or L1CAM stimulation. Hence, TRPV2\'s calcium signaling plays a previously undescribed, yet vital role in cell adhesion, and TRPV2 calcium flux and neurite development are intricately linked via NCAM and L1CAM cell adhesion proteins.
摘要：
TRPV2电压不敏感，钙渗透离子通道在癌症进展中发挥重要作用，免疫反应，和神经元发育。尽管TRPV2的生理影响，介导TRPV2反应和受影响的信号通路的潜在内源性蛋白仍然难以捉摸.使用定量过氧化物酶催化（APEX2）邻近蛋白质组学，我们揭示了TRPV2近端蛋白质组中的动态变化，并鉴定了响应激活而募集到分子通道附近的钙信号和细胞粘附因子。定量TRPV2邻近蛋白质组学进一步揭示了在神经和细胞投射中具有生物学功能的蛋白质簇的活化诱导富集。我们证明了TRPV2与神经免疫球蛋白细胞粘附分子NCAM和L1CAM之间的功能联系。NCAM和L1CAM刺激强烈诱导神经元PC12细胞中的TRPV2[Ca2]I通量，并且这种TRPV2特异性[Ca2]I通量需要激活蛋白激酶PKCα。TRPV2表达直接影响由NCAM或L1CAM刺激调节的神经突长度。因此，TRPV2的钙信号发挥了以前未描述的作用，然而在细胞粘附中起着至关重要的作用，和TRPV2钙通量和神经突发育通过NCAM和L1CAM细胞粘附蛋白错综复杂地联系在一起。
