Emerging role of junctophilin-2 as a regulator of calcium handling in the heart

Abstract

Junctophilin-2 (JPH2) is a membrane-binding protein that plays a key role in the organization of the junctional membrane complex (JMC) in cardiac myocytes. JPH2 is believed to keep the plasma membrane and sarcoplasmic reticulum at a fixed distance within the JMC, which is essential for proper Ca(2+)-induced Ca(2+) release during the excitation-contraction process. Recent studies have revealed that mutations in the JPH2 gene are associated with hypertrophic cardiomyopathy, highlighting the importance of this protein for normal cardiac physiology. In this paper, we review current knowledge about the structure and function of junctophilin-2 in the heart.

Figure 1

Schematic representation of a junctional membrane complex (JMC) in cardiac myocytes, showing voltage-gated Ca²⁺ channels (VGCC, also known as L-type Ca²⁺ channels), cardiac ryanodine receptors (RyR2), and junctophilin-2 (JPH2) proteins. The inset depicts the proposed structural domains of JPH2. PM, plasma membrane; SR, sarcoplasmic reticulum; TMD, transmembrane domain.

Figure 2

Overview of the flow of calcium within the junctional membrane complex during excitation-contraction coupling. Plasma membrane (PM) depolarization triggers the opening of voltage-gated Ca²⁺ channels (VGCC), allowing influx of calcium ions. This triggers the release of a greater amount of Ca²⁺ from the sarcoplasmic reticulum (SR) via ryanodine receptors (RyR2). After Ca²⁺-induced contraction of the sarcomere, myocyte relaxation occurs when calcium ions are pumped back into the SR by sarco/endoplasmic reticulum Ca²⁺ ATPase (SERCA) or removed from the myocyte by the Na⁺/Ca²⁺ exchanger (NCX). Proper structure and function of junctophilin-2 (JPH2) is believed to be essential for proper excitation-contraction coupling in cardiac myocytes.