Hot topics: High resolution structure of the voltage-gated skeletal muscle Ca2+ channel complex

In a recent article in Nature [1], Wu et al. present the cryo-electron microscopy structure of the rabbit Cav1.1 complex at a nominal resolution of 3.6 Å. Enrichment of purified channel particles without carbon film increased resolution and allowed to delineate structural features of the channel beyond those published by the authors in Science [2] six months earlier. The new structure reveals the channel in a (most likely) inactivated state (pore closed, voltage-sensors “up”), provides more complete structural detail of the α2δ-subunit and its interaction with extracellular surface of the pore-forming α1-subunit and unveils formation of a globular domain by direct interaction of the proximal C-terminal tail of α1 with its intracellular III-IV linker.
The new structural information provides new perspectives to address long-standing open questions. It will help to model human disease-related missense mutations within the Cav1.1 α1-subunit structure revealing the molecular mechanisms causing aberrant channel function, such as the formation of omega-pores in hypokalemic periodic paralysis [3]. The drug binding domains for Ca2+ channel blockers, widely used as antihypertensive drugs by blocking highly homologous Cav1.2 L-type channels in arterial resistance vessels, are highly conserved in Cav1.1. Together with recently published high resolution structure of the receptor sites for these drugs within the Ca2+-selective bacterial Na+-channel (NavAb) derivative CavAb [4], the new Cav1.1 structure will now allow to further refine the molecular details of drug interactions with L-type Ca2+ channels. The unexpected finding of a globular domain formed by the proximal C-terminus and the cytoplasmic III-IV linker of the pore subunit could provide the structural missing link for understanding how the C-terminus mediates protein kinase A regulation of the channel and controls voltage- and Ca2+-dependent channel gating in Cav1.1 and other voltage-gated Ca2+ channels.
Finally, it will be interesting to see how well the Cav1.1 α1-subunit structure was predicted by homology modeling using bacterial Na+-channels (like NavAb) or mammalian K+-channels as a template [5].

[1] Wu et al. (2016). Structure of the voltage-gated Ca2+ channel Cav1.1 at 3.6 Å resolution. Nature 537:191-196. [PMID 27580036].
[2] Wu et al. (2015). Structure of the voltage-gated calcium channel Cav1.1 complex. Science 350: aad2395. [PMID 26680202].
[3] Wu et al. (2012). A calcium channel mutant mouse model of hypokalemic periodic paralysis. J. Clin. Invest. 122: 4580–4591. [PMID 23187123].
[4] Tang et al. (2016). Structural basis for inhibition of a voltage-gated Ca(2+) channel by Ca(2+) antagonist drugs. Nature 537: 117–121. [PMID 27556947].
[5] Tuluc et al. (2016). Molecular interactions in the voltage sensor controlling gating properties of Cav calcium channels. Structure 24:261–271. [PMID 26749449].

Comments by Jörg Striessnig (Department of Pharmacology and Toxicology – Institute of Pharmacy, Universität Innsbruck)

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