Cooperative and acute inhibition by multiple C-terminal motifs of L-type Ca2+ channels.

Nan Liu,Min Liu,Henry M Colecraft,Yaxiong Yang,Lin Ge,Xiaodong Liu

doi:10.7554/elife.21989

Nan Liu, Min Liu + Show 4 more

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https://doi.org/10.7554/elife.21989

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Journal: eLife	Publication Date: Jan 6, 2017
Citations: 13	License type: CC BY 4.0

Affiliation: Tsinghua University, Columbia University

Abstract

Inhibitions and antagonists of L-type Ca2+ channels are important to both research and therapeutics. Here, we report C-terminus mediated inhibition (CMI) for CaV1.3 that multiple motifs coordinate to tune down Ca2+ current and Ca2+ influx toward the lower limits determined by end-stage CDI (Ca2+-dependent inactivation). Among IQV (preIQ3-IQ domain), PCRD and DCRD (proximal or distal C-terminal regulatory domain), spatial closeness of any two modules, e.g., by constitutive fusion, facilitates the trio to form the complex, compete against calmodulin, and alter the gating. Acute CMI by rapamycin-inducible heterodimerization helps reconcile the concurrent activation/inactivation attenuations to ensure Ca2+ influx is reduced, in that Ca2+ current activated by depolarization is potently (~65%) inhibited at the peak (full activation), but not later on (end-stage inactivation, ~300 ms). Meanwhile, CMI provides a new paradigm to develop CaV1 inhibitors, the therapeutic potential of which is implied by computational modeling of CaV1.3 dysregulations related to Parkinson's disease.

Highlights

L-type Ca2+ channels (LTCC or CaV1 channels) play pivotal roles in numerous physiological functions by mediating Ca2+ influx and membrane excitability (Striessnig et al, 2014)
By way of distal carboxyl tail (DCT) competition against apoCaM, the provisional C-terminus mediated inhibition (CMI) was expected to attenuate both SCa and JCa, as suggested by prior studies (Liu et al, 2010; Singh et al, 2008, 2006; Tan et al, 2011, 2012; Wahl-Schott et al, 2006). Most of these reports focused on either Ca2+-dependent inactivation (CDI) or voltage-gated activation (VGA) only; or even when both were studied for whole-cell its Ca2+ current (ICa), CDI and VGA were separately evaluated with different experimental groups
This study focuses on the principle of CMI mediated by multiple carboxyl-tail motifs to compete apoCaM off the channel

Summary

Introduction

L-type Ca2+ channels (LTCC or CaV1 channels) play pivotal roles in numerous physiological functions by mediating Ca2+ influx and membrane excitability (Striessnig et al, 2014). CaV1.3 is tuned by its own distal carboxyl tail (DCT) to compete with apoCaM (Ca2+-free calmodulin), which is pre-associated with the carboxyl terminus of the channel at preIQ3-IQ domain (denoted as IQV). Involved in both apoCaM and Ca2+/CaM binding (Jurado et al, 1999), IQV plays important roles in channel functions (Ben Johny et al, 2013; Liu et al, 2010; Singh et al, 2006; Wahl-Schott et al, 2006).

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