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Review
. 2015 Jun 5;116(12):1971-88.
doi: 10.1161/CIRCRESAHA.116.305017.

Ion channel macromolecular complexes in cardiomyocytes: roles in sudden cardiac death

Hugues Abriel  1 , Jean-Sébastien Rougier  1 , José Jalife  2
Affiliations
Review

Ion channel macromolecular complexes in cardiomyocytes: roles in sudden cardiac death

Hugues Abriel et al. Circ Res. .

Abstract

The movement of ions across specific channels embedded on the membrane of individual cardiomyocytes is crucial for the generation and propagation of the cardiac electric impulse. Emerging evidence over the past 20 years strongly suggests that the normal electric function of the heart is the result of dynamic interactions of membrane ion channels working in an orchestrated fashion as part of complex molecular networks. Such networks work together with exquisite temporal precision to generate each action potential and contraction. Macromolecular complexes play crucial roles in transcription, translation, oligomerization, trafficking, membrane retention, glycosylation, post-translational modification, turnover, function, and degradation of all cardiac ion channels known to date. In addition, the accurate timing of each cardiac beat and contraction demands, a comparable precision on the assembly and organizations of sodium, calcium, and potassium channel complexes within specific subcellular microdomains, where physical proximity allows for prompt and efficient interaction. This review article, part of the Compendium on Sudden Cardiac Death, discusses the major issues related to the role of ion channel macromolecular assemblies in normal cardiac electric function and the mechanisms of arrhythmias leading to sudden cardiac death. It provides an idea of how these issues are being addressed in the laboratory and in the clinic, which important questions remain unanswered, and what future research will be needed to improve knowledge and advance therapy.

Keywords: arrhythmias, cardiac; death, sudden, cardiac; ion channels; multiprotein complexes.

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Figures

Figure 1
Figure 1
Topography of NaV1.5 channel and its interacting proteins. The proteins for which a binding site has been mapped are represented: 14-3-3 protein _-isoform, calmodulin-dependent protein kinase II delta-c, MOG1, ankyrin-g, fibroblast growth factor like 13, calmodulin, Nedd4-2 like ubiquitin ligases, syntrophin proteins adapting either dystrophin or utrophin, protein tyrosine phosphatase-H1, synapse associated protein-97. The proteins with question marks were found to interact with NaV1.5 but the sites of interaction are not yet known (CAR is coxsackie and adenovirus receptor, Desmogl-2 is desmoglein-2). Only one of the four beta subunits is represented (in red).
Figure 2
Figure 2
(A) Proximity ligation assay staining using antibodies for NaV1.5 and pan-syntrophin demonstrating the specific location of the interaction between these two proteins at the lateral membranes of mouse cardiac cells (red dots). In green, immunofluorescence staining demonstrating the present of connexin-43 at the IDs (modified with permission from Shy et al. 2014). (B) Depending on the partner proteins they interact with, NaV1.5 is found either at the ID region, or at the lateral membrane (composed of crest regions and T-tubules) of cardiomyocytes. Along the crests, functional sodium channels do not distribute homogenously, but segregate in densely-populated clusters, coexisting with areas devoid of functional channels.
Figure 3
Figure 3
(Upper panels) Isolated mouse ventricular myocyte with double immunofluorescence staining (imaged with confocal microscopy). NaV1.5 (green) is expressed at the IDs, lateral membrane. The punctate staining most-likely represents the expression at the t-tubules. Syntrophin is only expressed at the lateral membrane where it co-localize with NaV1.5 (see arrow in merge showing the yellow region of co-localization). (Lower panels) Stainings of myocytes from genetically-modified mice (truncation of the last three residues of NaV1.5 interacting with syntrophins and SAP97, ΔSIV) illustrating the reduction of Nav1.5 expression exclusively at the lateral membrane, (modified with permission from Shy et al. 2014).
Figure 4
Figure 4
Cav1.2 channels subunits (Cavα1, Cavβ, Cavα2-δ, and Cavγ) and their major interacting proteins. Ahnak1, Nedd4-1 (Neural precursor cell Expressed, Developmentally Down-regulated 4-1), RGK (Rem, Rem2, Rad, and Gem/Kir), Cav-3 (caveolin-3), PKA (protein kinase A), CaMKII (Ca2+/calmodulin-dependent protein kinase II), and USP2-45 (Ubiquitin carboxyl-terminal hydrolase 2 isoform 45). ). Illustration credit: Ben Smith.
Figure 5
Figure 5
Scheme showing the protein composition of the three CaV1.2-macromolecular complexes (dyad, extra-dyad, and extra t-tubule). (1) The extra-t-tubule; CaV1.2 channels and CaV-3 (caveolin-3) (2) The extra-dyad: CaV1.2 channels, Bin1 (bridging Integrator 1/amphiphysin 2), dysferlin, β2-AR (β2-adrenergic receptor), ahnak1, and calcineurin, and (3) The dyad: CaV1.2 channels, RyR2 (type 2 ryanodine receptor), sorcin, and JPH2 (junctophilin 2). Illustration credit: Ben Smith.
Figure 6
Figure 6
NaV1.5 and Kir2.1 form a macromolecular complex (a channelosome). The subcellular localization and channel activity of both NaV1.5 and Kir2.1 are regulated by protein–protein interactions by their respective carboxyl terminal (CT) PDZ binding motifs with such PDZ domain-containing proteins as SAP97 and syntrophin. The CTs of one NaV1.5 and Kir2.1 molecule each bind to the same SAP97 molecule but at different PDZ domains. These interactions result in changes in the expression of NaV1.5 and/or Kir2.1 and thereby, influence their function in the cell membrane. GK, guanylate kinase-like domain of SAP97; SE/AI, last 3 residues of the Kir2.1 CT, which can be serine and glutamic acid or alanine and isoleucine; SH3, src kinase homology domain of SAP97; SIV, serine, isoleucine, Q:5 valine (last 3 aa of the NaV1.5 CT). Reproduced from Milstein et al, PNAS 2012 (ref 9).
Figure 7
Figure 7
Electrophysiological alterations in SAP97 knock-out ventricular cardiac cells (modified with permission from Gillet et al. HRJ 2015 (ref 26). (A) Marked prolongation of the mouse cardiac AP in SAP97-deficient cardiac cells (KO in red and WT in black). Decrease of whole-cell IK1 (B), Ito (C), and Ikur (D) currents in in SAP97-deficient cardiac cells. These decreased repolarization currents are the main causes of the AP prolongation. Phase 0 of the AP, i.e. the dV/dt, was not altered consistent with observation that INa was not modified in the absence of SAP97.
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