SPEG: a key regulator of cardiac calcium homeostasis

Abstract

Proper cardiac Ca2+ homeostasis is essential for normal excitation-contraction coupling. Perturbations in cardiac Ca2+ handling through altered kinase activity has been implicated in altered cardiac contractility and arrhythmogenesis. Thus, a better understanding of cardiac Ca2+ handling regulation is vital for a better understanding of various human disease processes. 'Striated muscle preferentially expressed protein kinase' (SPEG) is a member of the myosin light chain kinase family that is key for normal cardiac function. Work within the last 5 years has revealed that SPEG has a crucial role in maintaining normal cardiac Ca2+ handling through maintenance of transverse tubule formation and phosphorylation of junctional membrane complex proteins. Additionally, SPEG has been causally impacted in human genetic diseases such as centronuclear myopathy and dilated cardiomyopathy as well as in common acquired cardiovascular disease such as heart failure and atrial fibrillation. Given the rapidly emerging role of SPEG as a key cardiac Ca2+ regulator, we here present this review in order to summarize recent findings regarding the mechanisms of SPEG regulation of cardiac excitation-contraction coupling in both physiology and human disease. A better understanding of the roles of SPEG will be important for a more complete comprehension of cardiac Ca2+ regulation in physiology and disease.

Keywords: Atrial fibrillation; Cardiomyopathy; Centronuclear myopathy; Excitation–contraction coupling; Heart failure; JPH2; Ryanodine receptor; SERCA2a; Striated muscle preferentially expressed protein kinase.

Figure 1

Tissue-specific isoforms of SPEG and functional domains. (A) Diagram of the SPEG complex locus (top) along with the gene regions transcribed for each isoform. Black arrows mark alternative transcription start sites. Red-filled boxes are protein coding sequences/exons. Clear boxes code untranslated regions. Tissue-specific transcripts with exons/sequences included are indicated below the gene diagram. Adult tissues expressing high levels of the transcripts are indicated to the left. (B) Diagram of full-length canonical SPEG protein showing key domains including immunoglobulin, fibronectin III and kinase domains. The lines below the diagram indicate which domains are part of the four SPEG isoforms (SPEGβ, SPEGα, APEG-1, and BPEG) marked below. Scale bar of 200 amino acids (a.a.).

Figure 2

Subcellular organization of SPEG and its phosphorylation targets in cardiac muscle. SPEG phosphorylation of junctophilin-2 (JPH2) in cardiac muscle plays a role in T-tubule formation and stabilization. SPEG phosphorylation of RyR2 and SERCA2a in cardiac muscle modulates sarcoplasmic reticulum Ca²⁺ handling.

Figure 3

SPEG phosphorylation of RyR2-S2367 inhibits diastolic Ca²⁺ leak. While CaMKII phosphorylation (P) of S2814 and PKA phosphorylation of S2808 and S2030 have been shown to enhance RyR2 diastolic opening, enhanced targeting by protein phosphatase 1 and 2 (PP1 and PP2) along with phosphorylation of S2367 by SPEG inhibit diastolic Ca²⁺ leak.

Figure 4

Localization of SPEG mutation associated with human disease. Diagram showing SPEG mutations identified in patients (P) 1-11 reported to date (see Table 2) relative to the functional protein domains. All protein domains are drawn to scale. *Nonsense mutation. Fs, frameshift.