演讲人CV：

The divergence of Ca_V channels (voltage-gated Ca²⁺ channels) is well manifested by versatile termini. Certain distal carboxy tails (DCT) are recently reported as inhibitory modules of CDI (Ca²⁺ dependent inactivation, mediated by calmodulin, i.e., CaM). However, such inhibitions of CDI, only valid within rather limited subset of channels, are considered as exceptions; whereas for the majority, CDI is regulated exclusively by CaM binding motifs in the channel other than DCT. Also, each CaM is assumed to be bound with one channel as avidly as one subunit, despite the fact that CaM concentration ([CaM]) is biologically adjustable. Partly compounded with above prevalent concepts, the mechanism of DCT remains elusive. Here, a convergent scheme of competition, quantitatively unified across DCT isoforms, is depicted to embrace DCT as indispensable element into the core mechanism of CDI, enlightened by two major discoveries. First, Ca²⁺ feedback is tuned by [CaM], initially hinted by certain Ca_V1.4 mutation in congenital stationary night blindness. Second, the strict competition between DCT and CaM resembles classic enzyme inhibition, and readily extends to other DCT, such as the DCT of human Ca_V1.3, and even to rat Ca_V1.3 (exhibiting no different CDI from short Ca_V1.3 in prior reports). Combining electrophysiology with optical sensor measurement in single intact cells, levels of CDI are correlated with [CaM] in situ. Tuning curves from such novel quantification for DCT variants, together with FRET assay of key channel motifs, strongly argue that divergent tails essentially converge into a coherent toolset of CaM competitors varying in strength. The approach to quantify mechanistic linkage of diverse genes and the quantitative in situ binding assay for macromolecules, are both promising to be extendible for broader applicability. Beyond above significance, this tuning mechanism holds major consequences for calcium regulation throughout the body, with important implications for both cardiac diseases such as arrhythmias and heart failure and neurodegenerative diseases including Parkinson`s, Alzheimer`s, and schizophrenia.