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Review
. 2018 Jan 1:192:278-285.
doi: 10.1016/j.lfs.2017.11.009. Epub 2017 Nov 9.

The role of βII spectrin in cardiac health and disease

Mohamed H Derbala  1 , Aaron S Guo  2 , Peter J Mohler  3 , Sakima A Smith  4
Affiliations
Review

The role of βII spectrin in cardiac health and disease

Mohamed H Derbala et al. Life Sci. .

Abstract

Spectrins are large, flexible proteins comprised of α-β dimers that are connected head-to-head to form the canonical heterotetrameric spectrin structure. Spectrins were initially believed to be exclusively found in human erythrocytic membrane and are highly conserved among different species. βII spectrin, the most common isoform of non-erythrocytic spectrin, is found in all nucleated cells and forms larger macromolecular complexes with ankyrins and actins. Not only is βII spectrin a central cytoskeletal scaffolding protein involved in preserving cell structure but it has also emerged as a critical protein required for distinct physiologic functions such as posttranslational localization of crucial membrane proteins and signal transduction. In the heart, βII spectrin plays a vital role in maintaining normal cardiac membrane excitability and proper cardiac development during embryogenesis. Mutations in βII spectrin genes have been strongly linked with the development of serious cardiac disorders such as congenital arrhythmias, heart failure, and possibly sudden cardiac death. This review focuses on our current knowledge of the role βII spectrin plays in the cardiovascular system in health and disease and the potential future clinical implications.

Keywords: Ankyrin; Cytoskeleton; Spectrin; βII spectrin.

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Conflict of interest statement

Conflict of interest statement

The authors declare that there are no conflicts of interest.

Figures

Fig. 1
Fig. 1
A schematic view of a normal cardiomyocyte and a βII spectrin knockout cardiomyocyte. In the absence of βII spectrin protein, the expression levels of ryanodine receptor 2 (RyR2), Na+-K+-ATPase and Na+-Ca2 +-exchanger (NCX), Ankyrin-B (Ank-B), αII spectrin are significantly decreased and showed defective localization [20]. The expression of both sarco/endoplasmic reticulum Ca2 +-ATPase (SERCA2) and voltage-gated Na+ channel (Nav1.5) are not impacted by the loss of βII spectrin [20]. Additionally, both SERCA2 and L-Type Ca2 + channel (LTCC) are properly localized. The levels of Ankyrin-G (Ank-G) are increased in the absence of βII spectrin, likely as a compensatory response to decrease ankyrin-B expression [20]. Defects in ryanodine receptors result in aberrant Ca2 +-dependent release and subsequent spontaneous afterdepolarizations which eventually lead to the development of arrhythmias. In a murine model of a cKO of βII spectrin, ryanodine was shown to inhibit Ca2+ release and abolishes these spontaneous afterdepolarizations. It is important to note that further research is warranted to demonstrate the localization of Nav1.5 and the expression of LTCC in βII spectrin deficiency. In addition, no data are currently available that directly links the expression and localization of inositol triphosphate receptor (InsP3R), a known ankyrin-B binder, to βII spectrin protein. However, mislocalization and decreased expression of InsP3R is expected due to decreased ankyrin-B expression [101,102].
Fig. 2
Fig. 2
A schematic view of a cardiomyocyte during acute myocardial injury. In the event of acute myocardial damage, Ca2 + dysregulation occurs leading to Ca2 + leak from the sarcoplasmic reticulum and subsequent activation of calpain and caspase enzymes. Increased levels of reactive oxygen species (ROS) released within the cardiomyocyte also activate Ca2 +dependent proteases. These proteases then cleave βII spectrin (denoted by red star) and other potential protein substrates (denoted by green stars) producing βII spectrin breakdown products (SBDPs) which could have translational potential as a biomarker of cardiac damage via detection in blood or urine. SBDPs could serve as early biomarkers in acute cardiac injury that would aid in the diagnosis, surveillance, and monitoring of patients who have acute cardiac syndromes. Of note the calpain inhibitor MDL-28170 prevents the degradation of βII spectrin, and this could serve as a therapeutic intervention for the stabilization of βII spectrin following acute cardiac injury [20]. (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.)
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