University of Calgary PRISM: University of Calgary's Digital Repository Cumming School of Medicine Cumming School of Medicine Research & Publications 2011-09 Signaling complexes of voltage-gated calcium channels Turner, Ray W.; Anderson, Dustin M.; Zamponi, Gerald W. Taylor and Francis Turner, R. W., Anderson, D., & Zamponi, G. W. (2011). Signaling complexes of voltage-gated calcium channels. Channels. Taylor and Francis Inc. https://doi.org/10.4161/chan.5.5.16473 http://hdl.handle.net/1880/106654 unknown https://creativecommons.org/licenses/by/4.0 Downloaded from PRISM: https://prism.ucalgary.ca review REVIEW Channels 5:5, 1-9; September/October 2011; © 2011 Landes Bioscience Signaling complexes of voltage-gated calcium channels Ray W. Turner,1 Dustin Anderson1,2 and Gerald W. Zamponi2,* 1Department of Cell Biology and Anatomy; 2Department of Physiology and Pharmacology; Hotchkiss Brain Institute; University of Calgary; Calgary, AB Canada Key words: calcium channels, G proteins, potassium channels, calcium, GPCR Voltage-gated calcium channels are key mediators of contraction coupling in the heart and muscle, insulin secretion depolarization induced calcium entry into electrically and calcium dependent gene transcription.17-21 Along these lines, excitable cells. There is increasing evidence that voltage-gated different calcium channels isoforms are targeted by clinically calcium channels, like many other types of ionic channels, active drugs such as analgesics, general anesthetics, antiepileptics do not operate in isolation, but instead form complexes with 12,15,22-24 signaling molecules, G protein coupled receptors, and other and cardioactive drugs, and mutations in various calcium types of ion channels. Furthermore, there appears to be channel isoforms have been associated with conditions such as bidirectional signaling within these protein complexes, thus familial migraine, deafness, epilepsy, cardiac arrhythmias and allowing not only for efficient translation of calcium signals ataxia (reviewed in refs. 25 and 26). into cellular responses, but also for tight control of calcium Common to all types of voltage-gated calcium channels is entry per se. In this review, we will focus predominantly on a pore forming Cavα1 subunit that contains four homologous signaling complexes between G protein-coupled receptors membrane domains that are flanked by cytoplasmic N- and and high voltage activated calcium channels, and on C-termini and connected by cytoplasmic linker regions.9 While complexes of voltage-gated calcium channels and members T-type calcium channels are thought to contain only a Ca α1 of the©2011 potassium channel superfamily. Landes Bioscience.v subunit, members of the HVA calcium channel family also con- tain a cytoplasmic Cavβ subunit, as well as a larger extracellular membrane anchored Cavα2δ subunit, and both of these subunits are represented by four different genes (reviewed in refs. 27 and IntroductionDo not distribute.28). This coassembly with ancillary subunits is necessary in order to promote export of the channels from the endoplasmic reticu- Calcium ions serve as important mediators of cell signaling in lum,29 and also results in alteration of the functional properties both excitable and non-excitable tissues. Elevation in intracel- of the channels.27,30 In addition, all of the known HVA chan- lular calcium levels triggers physiological responses that include nels co-assemble with calmodulin, a calcium binding protein cardiac muscle contraction, hormone secretion, neurotransmitter that bestows calcium feedback regulation onto the channels in release, activation of calcium-dependent enzymes and calcium the form of calcium-dependent inactivation and facilitation.31-33 dependent gene transcription.1-5 In electrically excitable cells such The incorporation of a calcium signaling protein into the chan- as neurons and muscle cells, action potential evoked calcium nel complex is indicative of the notion that calcium channels do entry is primarily due to the activation of both low and high volt- not operate in isolation, but tend to form larger signaling com- age-gated calcium channels.6 Low voltage activated (LVA),7 and plexes that are not only designed to enhance coupling efficiency high voltage activated (HVA) calcium channels can be distin- between calcium entry and downstream signaling events, but also guished based on their threshold of activation, with LVA chan- provide for a means of regulating calcium channel activity per se. nels activating close to resting membrane potentials.8 In contrast, There are numerous examples of cytoplasmic protein inter- the family of HVA channels that includes subtypes such as L-, actions with different types of voltage-gated calcium channels. N-, P/Q- and R-types require larger membrane depolarizations For example, N and P/Q-type calcium channels tightly associate 9 This manuscript has been published online, prior to printing. Once the issue is complete and page numbers have been assigned, the citation will change accordingly. the issue is complete and page numbers have Once to printing. has been published online, prior This manuscript in order to open. Individual calcium channel subtypes differ in with proteins of the synaptic vesicle release machinery, such as their cellular and subcellular distributions, functional proper- syntaxin 1 and SNAP-25, thus effectively coupling calcium entry ties and pharmacological profiles.10-13 They also support distinct to fast vessel release, but also to confer feedback regulation onto physiological functions. For example, T-type calcium channels channel activity.34-38 Small GTPases such as Rem, Gem and Rem2 are involved in regulating cellular excitability,14-16 N and P/Q- associate with HVA channels to regulate channel surface expres- type channels mediate fast evoked neurotransmitter release,1 and sion (reviewed in ref. 39). A-Kinase anchoring proteins, protein L-type calcium channels mediate functions such as excitation kinase A, and phosphatase 2A associate with certain L-type chan- nel isoforms to tightly control the regulation of channel activity by *Correspondence to: Gerald W. Zamponi; Email: [email protected] phosphorylation.40-43 However, it has only emerged recently that Submitted: 07/05/11; Revised: 07/16/11; Accepted: 07/20/11 various types of calcium channels interact not only with cytoplas- DOI: mic signaling molecules, but also with other membrane proteins www.landesbioscience.com Channels 1 such as receptors and ion channels to form physical signaling three known βAR subtypes expressed in the mammalian heart complexes that either allow for more efficient regulation of cal- (β1AR, β2AR, β3AR),58 with the β1AR and β2AR subtypes cium channel activity or facilitate the specificity of calcium sig- able to activate PKA and stimulate calcium entry via L-type cal- naling.44 Here we will focus on two such examples: We will first cium channels into cardiac myocytes.59-61 It has been shown that discuss how protein interactions with G protein coupled recep- β2ARs form macromolecular signaling complexes with Cav1.2 tors enhance calcium channel modulation and trafficking. We calcium channels.62 These complexes also contain other ele- will then review how interactions between calcium channels and ments of the signaling machinery, such as G proteins and caveo- potassium channels bestow calcium regulation onto potassium lin. The functional significance of these assemblies has not yet channel function and thus modify neuronal output. been demonstrated in cardiac myocytes, nor have the molecu- lar determinants that underlie the interactions between L-type G Protein Coupled Receptor—Calcium Channel calcium channels and receptors been identified. The investiga- Complexes tion into coupling between these receptors and the channels has been hampered by the fact that it has proven to be a challenge Most types of voltage-gated calcium channels are modulated fol- to reconstitute βAR signaling to L-type channels in heterolo- lowing the activation of various types of G protein coupled receptors gous systems—a problem that has only been solved recently.40 (GPCRs) (reviewed in refs. 45 and 46). Upon receptor activation, Nonetheless, the existence of receptor-Cav1.2 channel complexes GDP bound constitutively to the Gα subunit is exchanged for suggests that they may help optimize the coupling between the GTP, resulting in a conformational change that either leads to a receptor and the channels. breakup of the Gαβγ trimer, or at the least in a conformational change within the trimer that results in the generation of two sepa- P/Q-Type Channels rate signaling entities—activated Gα and Gβγ dimers. Both Gα and Gβγ act on various effector molecules. For example, Gαs may Like N-type calcium channels, P/Q-type channels can be regu- stimulate the activity of adenylyl cyclase, leading to the produc- lated by a membrane delimited Gβγ mediated pathway in response tion of cyclic AMP and the activation of protein kinase A.47 In to activation of a number of different receptor subtypes. These the context©2011 of voltage-gated calcium channels,Landes a classic example channels Bioscience. are expressed at high levels in cerebellar Purkinje neu- of such a soluble second messenger pathway is the regulation of rons where they are regulated by activation of metabotropic glu- 63-65 L-type calcium channels by β-adrenergic receptors (βARs), which tamate receptors. Coexpression of these receptors with Cav2.1 results in protein kinase A dependent phosphorylation of the chan-