Feedback control of sodium and calcium channels – from shared molecular underpinnings to synthetic modulation.
Manu Ben-Johny, Ph.D.
Department of Bioengineering
Johns Hopkins University
The voltage-gated sodium (NaV) and calcium (CaV) channels constitutes two major ion-channel superfamilies with custom molecular attributes that enable a multitude of unique biological functions. For example, the NaV channels support brisk spatial propagation of action potentials while the CaV channels couple excitability to contraction, secretion, and transcription. Yet, one similarity of these channels is their homologous carboxy-tail, a segment that is a hotspot for diverse cardiac arrhythmogenic and neurological disorders. If this region were to support like-functions, deep mechanistic insights could be gleaned from the joint investigation of these channels, and shared principles derived for approaching related channelopathic diseases. For CaV channels, dynamic interactions between their tail domains and calmodulin elaborate rapid and recognizably similar forms of Ca2+-feedback regulation. However, for NaV channels, Ca2+ effects have long-appeared to be subtle and variable with divergent purported mechanisms, dimming prospects for unification. Here, using quantitative Ca2+-photouncaging and single-channel recordings, we show that these differences are only apparent and that Ca2+ regulatory function and mechanism are fundamentally conserved across the two channel families. Despite this high similarity and dependence on a modular structural element, we demonstrate how cells employ distinct auxiliary proteins to selectively switch feedback control of NaV versus CaV channels and vice versa. Overall, these results help substantiate the persistence of an ancient Ca2+-regulatory design across channel superfamilies, unravel the sophisticated mechanisms by which cytosolic proteins tune cellular excitability and calcium signaling, and reveal new strategies to engineer the molecular function of ion channels.
host: Stan Froehner