Emerging roles of junctophilin-2 in the heart and implications for cardiac diseases

Abstract

Cardiomyocytes rely on a highly specialized subcellular architecture to maintain normal cardiac function. In a little over a decade, junctophilin-2 (JPH2) has become recognized as a cardiac structural protein critical in forming junctional membrane complexes (JMCs), which are subcellular domains essential for excitation-contraction coupling within the heart. While initial studies described the structure of JPH2 and its role in anchoring junctional sarcoplasmic reticulum and transverse-tubule (T-tubule) membrane invaginations, recent research has an expanded role of JPH2 in JMC structure and function. For example, JPH2 is necessary for the development of postnatal T-tubule in mammals. It is also critical for the maintenance of the complex JMC architecture and stabilization of local ion channels in mature cardiomyocytes. Loss of this function by mutations or down-regulation of protein expression has been linked to hypertrophic cardiomyopathy, arrhythmias, and progression of disease in failing hearts. In this review, we summarize current views on the roles of JPH2 within the heart and how JPH2 dysregulation may contribute to a variety of cardiac diseases.

Keywords: Arrhythmias; Heart failure; Junctional membrane complex; Junctophilin-2; T-tubule development.

Figure 1

Positive correlation between JPH2 expression and postnatal T-tubule development. (A) Di-8-ANEPPS staining of ventricular myocytes isolated from JPH2 knockdown, wild-type, and JPH2 overexpression mice at P5 (before T-tubule maturation) and P8 (after initiation of T-tubule maturation) showing increased T-tubule development with increasing levels of JPH2. Scale bar = 10 μm. Adapted from Reynolds et al. (B) Possible mechanism of normal T-tubule development involving CAV3, Bin1, and JPH2. The loss of JPH2 prevents anchoring of developing T-tubules to the SR and maturation Ca²⁺ of handling. Modified from Al-Qusairi and Laporte.

Figure 2

Defects in the JMC architecture with JPH2 down-regulation. (A) Normal coupling of LTCC and ryanodine receptors (RyR2) promoting efficient CICR (black arrows). (B) Down-regulation of JPH2 possibly due to up-regulation of miR-24 degradation of JPH2 mRNA leading to disruption of T-tubules and uncoupling of JMC-associated ion channels leading to decreased cardiac function. Model does not depict stoichiometric ratios.

Figure 3

Proposed mechanism of JPH2-linked RyR2 dysregulation in AF. (Left panel) Normal cardiac JMC structure and Ca²⁺ handling. (Center panel) Loss of stabilizing interaction between RyR2 and JPH2 by the E169K JPH2 mutation causes increased RyR2 diastolic Ca²⁺ leak causing depolarizing waves, DADs, and triggered AF. (Right panel) A decreased ratio of JPH2:RyR2 causes similar RyR2 gating instability leading to AF.