Abstract
Voltage-gated calcium channels (VGCCs) represent the sole mechanism to convert membrane depolarization into cellular functions like secretion, contraction, or gene regulation. VGCCs consist of a pore-forming α1 subunit and several auxiliary channel subunits. These subunits come in multiple isoforms and splice-variants giving rise to a stunning molecular diversity of possible subunit combinations. It is generally believed that specific auxiliary subunits differentially regulate the channels and thereby contribute to the great functional diversity of VGCCs. If auxiliary subunits can associate and dissociate from pre-existing channel complexes, this would allow dynamic regulation of channel properties. However, most auxiliary subunits modulate current properties very similarly, and proof that any cellular calcium channel function is indeed modulated by the physiological exchange of auxiliary subunits is still lacking. In this review we summarize available information supporting a differential modulation of calcium channel functions by exchange of auxiliary subunits, as well as experimental evidence in support of alternative functions of the auxiliary subunits. At the heart of the discussion is the concept that, in their native environment, VGCCs function in the context of macromolecular signaling complexes and that the auxiliary subunits help to orchestrate the diverse protein–protein interactions found in these calcium channel signalosomes. Thus, in addition to a putative differential modulation of current properties, differential subcellular targeting properties and differential protein–protein interactions of the auxiliary subunits may explain the need for their vast molecular diversity. J. Cell. Physiol. 999: 00–00, 2015. © 2015 The Authors. Journal of Cellular Physiology Published by Wiley Periodicals, Inc. J. Cell. Physiol. 230: 2019–2031, 2015. © 2015 Wiley Periodicals, Inc.
Highlights
Voltage-gated calcium channels (VGCCs) represent the sole mechanism to convert membrane depolarization into cellular functions like secretion, contraction, or gene regulation
Rab-interacting molecule 1 (RIM1) binding to the auxiliary b subunits has a scaffolding function, and modulates the current properties of the channel. It slows down voltage-dependent inactivation and shifts its voltage-dependence to hyperpolarizing potentials (Coppola et al, 2001). These findings indicate a dual function of auxiliary b subunits in anchoring synaptic vesicles to presynaptic VGCCs and in the modulation of the calcium current that triggers vesicle fusion
Whereas co-expression studies in heterologous cells highlighted the effects of auxiliary subunits on channel functions, in their native context the auxiliary subunits appear to be involved in orchestrating macromolecular signaling complexes involved in a multitude of calcium-regulated cell functions
Summary
Like other voltage-gated ion channels, they open in response to changes in membrane potential allowing the influx of calcium ions down a steep electro-chemical gradient (Fig. 1A) This cation current further depolarizes the cell and plays important roles in the generation and shaping of action potentials, like in cardiac myocytes and in many neurons. A number of up- and down-stream signaling processes require the presence of specific auxiliary subunit isoforms, indicating the importance of the large molecular diversity of calcium channel subunits beyond differential modulation of VGCC current properties.
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
