Structure-function of proteins interacting with the α1 pore-forming subunit of high-voltage-activated calcium channels.

Alan Neely,Patricia Hidalgo

doi:10.3389/fphys.2014.00209

Alan Neely, Patricia Hidalgo

Open Access

https://doi.org/10.3389/fphys.2014.00209

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Abstract

Openings of high-voltage-activated (HVA) calcium channels lead to a transient increase in calcium concentration that in turn activate a plethora of cellular functions, including muscle contraction, secretion and gene transcription. To coordinate all these responses calcium channels form supramolecular assemblies containing effectors and regulatory proteins that couple calcium influx to the downstream signal cascades and to feedback elements. According to the original biochemical characterization of skeletal muscle Dihydropyridine receptors, HVA calcium channels are multi-subunit protein complexes consisting of a pore-forming subunit (α1) associated with four additional polypeptide chains β, α2, δ, and γ, often referred to as accessory subunits. Twenty-five years after the first purification of a high-voltage calcium channel, the concept of a flexible stoichiometry to expand the repertoire of mechanisms that regulate calcium channel influx has emerged. Several other proteins have been identified that associate directly with the α1-subunit, including calmodulin and multiple members of the small and large GTPase family. Some of these proteins only interact with a subset of α1-subunits and during specific stages of biogenesis. More strikingly, most of the α1-subunit interacting proteins, such as the β-subunit and small GTPases, regulate both gating and trafficking through a variety of mechanisms. Modulation of channel activity covers almost all biophysical properties of the channel. Likewise, regulation of the number of channels in the plasma membrane is performed by altering the release of the α1-subunit from the endoplasmic reticulum, by reducing its degradation or enhancing its recycling back to the cell surface. In this review, we discuss the structural basis, interplay and functional role of selected proteins that interact with the central pore-forming subunit of HVA calcium channels.

Highlights

Electrical excitability and synaptic transmission rely on an extended repertoire of voltage-activated ion channels that respond to membrane depolarization by opening an ion-selective pathway across the membrane
The Src Homology 3 domain (SH3)-guanylate kinase (GK) core is widely viewed as the minimal unit for channel modulation including trafficking (Takahashi et al, 2004, 2005; He et al, 2007), in our work we found that recombinant GK was sufficient to restore normal channel gating of CaV2.3 channels expressed in Xenopus oocytes (Gonzalez-Gutierrez et al, 2008b)
We focused on protein-protein interactions with the central pore-forming subunits of HVA calcium channels that are thought to participate in the formation of channel complexes underlying L, N, P/Q, and R-type currents (Figure 7)

Summary

INTRODUCTION

Electrical excitability and synaptic transmission rely on an extended repertoire of voltage-activated ion channels that respond to membrane depolarization by opening an ion-selective pathway across the membrane. Sodium- and potassium-selective channels are mostly involved in the propagation and shaping of electrical signals while calcium channels that are activated during an action potential are responsible for translating changes in the voltage across the membrane into a local calcium increase. This calcium signal initiates a wide spectrum of physiological responses such as muscle contraction, secretion and synaptic transmission (Catterall, 2010). The first systematic nomenclature describing the 10 genes encoding for α1-subunits used a capital letter referring to the skeletal muscle as α1S and to the rest as α1A through α1I www.frontiersin.org

CaV channels interacting proteins

BETA SUBUNIT

GAMA SUBUNIT

CaM regulation of calcium channels is the relative orientation of

CONCLUDING REMARKS