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Location, location, regulation: a novel role for β-spectrin in the heart

Kevin J. Sampson and Robert S. Kass

Department of Pharmacology, College of Physicians and Surgeons, Columbia University, New York, New York, USA.

Address correspondence to: Robert S. Kass, Department of Pharmacology, Columbia University Medical Center, 630 W. 168th St., New York, New York 10032, USA. Phone: 212.305.3720; Fax: 212.305.3545; E-mail:

First published September 27, 2010

Voltage-gated Na+ channels (VGSCs) are responsible for the rising phase of the action potential in excitable cells, including neurons and skeletal and cardiac myocytes. Small alterations in gating properties can lead to severe changes in cellular excitability, as evidenced by the plethora of heritable conditions attributed to mutations in VGSCs highlighting the need to better understand VGSC regulation. In this issue of the JCI, Hund et al. identify the ability of a key structural protein, βIV-spectrin, to bind and recruit Ca2+/calmodulin kinase II to the channel at a cellular location key to successful action potential initiation and propagation, where it can mediate function and excitability.

See the related article beginning on page 3508.

The Na+ channel and disease

In excitable tissues, such as muscle, heart, and nerve, action potential (AP) initiation is most often accomplished by the opening of voltage-gated Na+ channels (VGSCs). VGSC activity is critical for normal impulse conduction and contributes to control of the duration and morphology of the cellular AP. VGSCs have a primary pore-forming α subunit that is a protein with 4 homologous domains, each with 6 transmembrane segments (Figure 1).

The α subunit of the cardiac Na+ channel.Figure 1

The α subunit of the cardiac Na+ channel. DI–DIV denotes the 4 homologous domains of the α subunit; S1–S6 denote the 6 transmembrane segments. S5 and S6 are the pore-lining segments, and the S4 helices (black) serve as voltage sensors. In the connecting loop between DIII and DIV, the 3 residues isoleucine, phenylalanine, and methionine (IFM) are known to play a key role in the fast inactivation process.

Inward Na+ current is typically the largest membrane current in excitable cells and must quickly inactivate to allow the cell to begin to repolarize. In myocytes, Nav1.5 (which is encoded by SCN5A) is the principal VGSC α subunit expressed. It is predominantly localized in the intercalated discs in order to contribute to successful propagation of APs and the normal sequence of excitation-contraction (Figure 2A). Pivotal and key roles of VGSC activity in human physiology have been highlighted by the discovery of inherited mutations in Na+ channel α subunit–encoding genes linked to numerous disease phenotypes in multiple systems. Examples include epilepsy, linked to Nav1.1; periodic paralysis, linked to Nav1.4; cardiac conduction disease, linked to Nav1.5; and long QT syndrome, linked to Nav1.5 (13). In cardiac tissue, loss of function of Nav1.5 channels can lead to cardiac conduction disease and Brugada syndrome, whereas mutations that disrupt or delay inactivation, allowing for more Na+ current at later phases of the AP, lead to long QT syndrome (2).

The macromolecular complex associated with the VGSC Nav1.5 in cardiac myocyFigure 2

The macromolecular complex associated with the VGSC Nav1.5 in cardiac myocytes. (A) Ankyrin-G brings the VGSC in complex with the actin-spectrin cytoskeleton at the cardiac intercalated discs, where they can participate in initiation and propagation of the cardiac AP. (B) In this issue of the JCI, Hund et al. show that βIV-spectrin recruits CaMKIIδ to the Nav1.5-ankyrin complex and that CaMKIIδ then modulates function via phosphorylation of a serine in the I–II linker (19). Binding sites for a number of interacting proteins are also shown. CaM, calmodulin; FHF1B, fibroblast growth factor homologous factor 1B; Nedd4, Nedd4-like ubiquitin-protein ligases.

Most VGSCs activate and inactivate completely within the first few milliseconds of the AP, thus very quickly reducing or eliminating their contribution to AP waveform. When VGSCs fail to inactivate normally, the resulting late (i.e., not inactivated) Na+ current provides a substantial inward current that prolongs AP duration (APD) and can lead to arrhythmia, either directly through the altered AP waveform or indirectly via altered intracellular Na+ concentrations. In recent years, a great deal of effort has been put into understanding the role of this late Na+ current and the therapeutic benefits of its blockade (4). Late Na+ current is preferentially blocked by a large number of drugs that interact with the pore-forming region of the α subunit at a well-described site that is bound by several local anesthetic drug molecules (57). In addition to a role in heritable disease (including long QT and epilepsy), emerging evidence has revealed that aberrant late Na+ current may play a role in the advanced stages of heart failure (8). Therefore, understanding not only the structures within the VGSC α subunit, but also the molecular identity of partner proteins that modify Na+ channel function is critical to the understanding of a number of complex disease phenotypes.

The Na+ channel as a macromolecular complex

Our understanding of ion channels as macromolecular complexes that tightly control channel function and regulation has grown in recent years (9). For example, in a number of PKA-sensitive ion channel complexes, the primary pore-containing subunit is in complex with an A kinase–anchoring protein (AKAP) that recruits kinase, phosphatases, and phosphodiesterases to control the local phosphorylation state (10).

VGSCs also form macromolecular complexes with the α subunit, having been shown to interact with numerous proteins, including a β subunit, ankyrin, syntrophin, dystrophin, fibroblast growth factor homologous factor 1B, calmodulin, and Nedd4-like ubiquitin-protein ligases (Figure 2B), all of which are involved in the regulation of channel activity, correct cellular localization, and biosynthesis and degradation of the α subunit (11, 12). Mutations in a number of these interacting proteins have been associated with inherited disease, including variants 4, 10, and 12 of long QT syndrome (13, 14).

Another protein shown to regulate VGSCs primarily in — but not limited to — cardiac muscle, including an effect on late Na+ current, is Ca2+/calmodulin kinase II (CaMKII; refs. 15, 16). In addition to having an effect on VGSC current, CaMKII has been shown to be upregulated in heart failure and may therefore be a therapeutic target (17, 18). In this issue of the JCI, Hund et al. use sequence analysis to identify βIV-spectrin as a CaMKII binding protein that participates in the Nav1.5 macromolecular complex in cardiac myocyte intercalated discs (ref. 19 and Figure 2B). Therefore, βIV-spectrin appears analogous to the more ubiquitous AKAPs in that it recruits a kinase to a local signaling environment involving an ion channel. Moreover, Hund et al. found that βIV-spectrin was required for the action of CaMKII on Nav1.5 (19). In mouse cardiomyocytes, abolishing CaMKII activity via a mutation in βIV-spectrin positively shifted baseline Na+ channel steady-state inactivation (SSI) and eliminated the late Na+ current and SSI shift normally induced by β-adrenergic receptor stimulation by isoproterenol. Hund and colleagues further demonstrated that this was caused by βIV-spectrin directly regulating CaMKII-mediated phosphorylation of a specific serine residue in the Nav1.5 I–II linker, S571. Consistent with the present understanding of the functional role of Na+ channel activity in the heart, the hyperpolarizing shift in SSI observed in mice expressing mutant forms of βIV-spectrin led to reduced excitability, and the decrease in late current resulted in shortened APD and a subsequent decrease in QT interval. The finding of Hund et al. that βIV-spectrin associated with CaMKII in cerebellar Purkinje neurons targeting it to the axonal initial segments — critical regions for the generation of APs in which VGSCs localize — suggests that the key modulatory roles of βIV-spectrin may very well exist in the brain, and perhaps other tissues, in addition to the heart.

Conclusions and perspective

There has been increasing understanding that ion channels do not exist on cell membranes simply as pore-forming proteins, but are instead in complex with a host of proteins that can influence the channel in a multitude of ways, including aiding channel targeting to specific subcellular regions, controlling the phosphorylation state of the channel, participating in biosynthesis and degradation of the channel, and altering channel gating allosterically. The present study by Hund et al. increases our understanding of the molecular identity of the complex controlling the phosphorylation state of the predominant cardiac VSGC (19). As phosphorylation of the channel affects channel-gating properties (i.e., SSI and late Na+ current), and small perturbations in these properties are linked to disease in a number of systems, understanding the molecular components in this pathway represents a significant contribution to the field. Subsequently, this molecular pathway may represent a novel therapeutic target or serve as a new locus for heritable channelopathies. Furthermore, the ability of βIV-spectrin to recruit CaMKII to distinct subcellular compartments critical to cellular excitability in other cell types may indicate a broader role within the cell, as it can serve not only as a structural protein, but also in the regulation of posttranslational states of membrane proteins.


The authors’ work is supported by National Heart, Lung, and Blood Institute, NIH, grant 2R01 HL 044365-18.


Conflict of interest: The authors have declared that no conflict of interest exists.

Citation for this article:J Clin Invest. 2010;120(10):3434–3437. doi:10.1172/JCI44810.

See the related article beginning on page 3508.


  1. Fischer TZ, Waxman SG. Familial pain syndromes from mutations of the NaV1.7 sodium channel. Ann N Y Acad Sci. 2010;1184:196–207.
    View this article via: PubMed CrossRef
  2. Ruan Y, Liu N, Priori SG. Sodium channel mutations and arrhythmias. Nat Rev Cardiol. 2009;6(5):337–348.
    View this article via: PubMed
  3. Catterall WA, Dib-Hajj S, Meisler MH, Pietrobon D. Inherited neuronal ion channelopathies: new windows on complex neurological diseases. J Neurosci. 2008;28(46):11768–11777.
    View this article via: PubMed CrossRef
  4. Belardinelli L, Shryock JC, Fraser H. Inhibition of the late sodium current as a potential cardioprotective principle: effects of the late sodium current inhibitor ranolazine. Heart. 2006;92(suppl 4):iv6–iv14.
    View this article via: PubMed
  5. Fozzard HA, Lee PJ, Lipkind GM. Mechanism of local anesthetic drug action on voltage-gated sodium channels. Curr Pharm Des. 2005;11(21):2671–2686.
    View this article via: PubMed CrossRef
  6. Bankston JR, Kass RS. Molecular determinants of local anesthetic action of beta-blocking drugs: Implications for therapeutic management of long QT syndrome variant 3. J Mol Cell Cardiol. 2010;48(1):246–253.
    View this article via: PubMed CrossRef
  7. Fredj S, Sampson KJ, Liu H, Kass RS. Molecular basis of ranolazine block of LQT-3 mutant sodium channels: evidence for site of action. Br J Pharmacol. 2006;148(1):16–24.
    View this article via: PubMed CrossRef
  8. Undrovinas A, Maltsev VA. Late sodium current is a new therapeutic target to improve contractility and rhythm in failing heart. Cardiovasc Hematol Agents Med Chem. 2008;6(4):348–359.
    View this article via: PubMed CrossRef
  9. Sampson KJ, Kass RS. Molecular mechanisms of adrenergic stimulation in the heart. Heart Rhythm. 2010;7(8):1151–1153.
    View this article via: PubMed CrossRef
  10. Carnegie GK, Means CK, Scott JD. A-kinase anchoring proteins: from protein complexes to physiology and disease. IUBMB Life. 2009;61(4):394–406.
    View this article via: PubMed CrossRef
  11. Abriel H, Kass RS. Regulation of the voltage-gated cardiac sodium channel Nav1.5 by interacting proteins. Trends Cardiovasc Med. 2005;15(1):35–40.
    View this article via: PubMed CrossRef
  12. Abriel H. Cardiac sodium channel Na(v)1.5 and interacting proteins: Physiology and pathophysiology. J Mol Cell Cardiol. 2010;48(1):2–11.
    View this article via: PubMed CrossRef
  13. Hedley PL, et al. The genetic basis of long QT and short QT syndromes: a mutation update. Hum Mutat. 2009;30(11):1486–1511.
    View this article via: PubMed CrossRef
  14. Hedley PL, et al. The genetic basis of Brugada syndrome: a mutation update. Hum Mutat. 2009;30(9):1256–1266.
    View this article via: PubMed
  15. Maltsev VA, Reznikov V, Undrovinas NA, Sabbah HN, Undrovinas A. Modulation of late sodium current by Ca2+, calmodulin, and CaMKII in normal and failing dog cardiomyocytes: similarities and differences. Am J Physiol Heart Circ Physiol. 2008;294(4):H1597–H1608.
    View this article via: PubMed CrossRef
  16. Wagner S, et al. Ca2+/calmodulin-dependent protein kinase II regulates cardiac Na+ channels. J Clin Invest. 2006;116(12):3127–3138.
    View this article via: PubMed CrossRef
  17. Maier LS, Bers DM. Calcium, calmodulin, and calcium-calmodulin kinase II: heartbeat to heartbeat and beyond. J Mol Cell Cardiol. 2002;34(8):919–939.
    View this article via: PubMed CrossRef
  18. Maier LS. Role of CaMKII for signaling and regulation in the heart. Front Biosci. 2009;14:486–496.
    View this article via: PubMed
  19. Hund TJ, et al. A βIV-spectrin/CaMKII signaling complex is essential for membrane excitability in mice. J Clin Invest. 2010;120(10):3508–3519.
    View this article via: