The Role of Ca2+ Signaling Proteins in CaV1-Mediated Excitation-Transcription Coupling

Abstract

L-type Ca2+ channels (CaV1) mediate prominent and specialized Ca2+ signals in response to membrane excitability, known as excitation-transcription (E-T) coupling (see review, Ma, Li and Tsien, 2015). A variety of Ca2+ signaling proteins (CaSP) have been suggested to involve in these processes, e.g., calmodulin (CaM) is able to continuously tune the gating of CaV1.3 channels by competing with the distal carboxyl tail of the channel (Liu et al. Nature 2010). Our data demonstrate that such tuning scheme can be expanded beyond CaM, by a number of other key signaling proteins that exert strong modulatory effects on CaV1 gating. Moreover, CaV1 complex containing CaM and newly discovered CaSPs underlies the critical steps of E-T coupling, e.g., bifurcation of Ca2+-CaV1 signals into segregated pathways, and physical coordination of CaV1/CaSPs in a dynamic manner (e.g., membrane-nucleus translocation) to achieve high specificity of signaling cascade. We here report the phenotypes and mechanisms for CaV1 gating modulations by both exogenous peptides from rational-design and endogenous CaSPs. In addition, taking cortical neurons as the model system, we further elucidate the signaling details of such CaV1/CaSP complex during E-T coupling.