ABSTRACT

Voltage-gated Ca²⁺ channels are typically integrated in a complex network of protein-protein-interactions, also referred to as Ca²⁺ channel nanodomains. Amongst the neuronal Ca_V2 channel family, Ca_V2.2 is of particular importance due to its general role for signal transmission from the periphery to the central nervous system, but also due to its significance for pain perception. Thus, Ca_V2.2 is an ideal target candidate to search for pharmacological inhibitors but also for novel modulatory interactors. In this review we summarize the last years findings of our intense screenings and characterization of the six Ca_V2.2 interaction partners, tetraspanin-13 (TSPAN-13), reticulon 1 (RTN1), member 1 of solute carrier family 38 (SLC38), prostaglandin D2 synthase (PTGDS), transmembrane protein 223 (TMEM223), and transmembrane BAX inhibitor motif 3 (Grina/TMBIM3) containing protein. Each protein shows a unique way of channel modulation as shown by extensive electrophysiological studies. Amongst the newly identified interactors, Grina/TMBIM3 is most striking due to its modulatory effect which is rather comparable to G-protein regulation.

摘要

电压门控 Ca ²⁺通道通常集成在复杂的蛋白质-蛋白质相互作用网络中，也称为 Ca ²⁺通道纳米域。在神经元 Ca _V 2 通道家族中，Ca _V 2.2 特别重要，因为它在从外周到中枢神经系统的信号传输中发挥一般作用，而且还因为它对疼痛感知具有重要意义。因此，Ca _V 2.2 是寻找药理抑制剂和新型调节相互作用物的理想靶标候选物。在这篇综述中，我们总结了过去几年我们对六种 Ca _{V进行密集筛选和表征的结果}2.2 相互作用伙伴，tetraspanin-13 (TSPAN-13)、reticulon 1 (RTN1)、溶质载体家族 38 的成员 1 (SLC38)、前列腺素 D2 合酶 (PTGDS)、跨膜蛋白 223 (TMEM223) 和跨膜 BAX 抑制剂基序 3 (Grina/TMBIM3) 含有蛋白质。广泛的电生理研究表明，每种蛋白质都显示出独特的通道调节方式。在新发现的相互作用因子中，Grina/TMBIM3 最为引人注目，因为它的调节作用与 G 蛋白调节相当。