JPH2 Membrane Protein Introduction

Introduction of JPH2

JPH2 is encoded by the JPH2 gene and is also known as Junctophilin-2, JP-2 and Junctophilin type 2. The JPH2 gene contains five coding exons localizing to 20q13.12 and encodes a 696 amino acid 74kDa protein JPH2 in humans. JPH2 is the major JPH family member expressed in cardiac muscle and shares significant primary sequence identity and functional parallels with JPH1 in skeletal muscle. From early studies, JPH2 was originally viewed as a structural protein serving as a molecular tether which maintained the cardiac dyad ultrastructure required for effective CICR and Ca²⁺ signaling. Recent studies have added complexity to the function of this protein.

Function of JPH2 Membrane Protein

JPH2 plays a critical role in maintaining this dyadic structure and associated effective Ca²⁺ signaling. The N-terminus of JPH2 localizes to the plasma membrane of the cardiomyocyte, binds plasmalemmal-limited Cav3 and directly interacts with RyR2 via the MORN motif joining region and possibly the C-terminal aspect of the protein. This interaction regulates RyR2 gating and is responsible for pathologic Ca²⁺ release in some JPH2 mutations. Together, these proteins along with other neighboring proteins, comprise the JMC. Besides, JPH2 null mice, while embryonic lethal, demonstrate a 90% increase in the distance of the cardiac dyad as well as vacuolization of the SR. Further, Ca²⁺ transients in JPH2 null mice are significantly reduced in amplitude perhaps due to the disruption of the SR ultrastructure. JPH2 plays a key role in cardiomyocyte development and differentiation. While it is possible that the amino-terminal MORN motifs of JPH2 might directly interact with the inner leaflet of the sarcolemma. In addition to Ca²⁺ signaling, JPH2 plays a key role in the development and stability of myocyte ultrastructure.

Fig.1 The signaling pathway of JPH2 in the Cardiac Myocyte (Landstrom, 2014).

Application of JPH2 Membrane Protein in Literature

1. Landstrom A.P., et al. The junctophilin family of proteins: From bench to bedside. Trends Mol. Med. 2014, 20(6):353-362. PubMed ID: 4636942
   
   

   This article reports that JPH2 plays a critical role in maintaining this dyadic structure and associated effective Ca²⁺ signaling. JPH2 is essential in cardiomyocyte development and differentiation. In addition to Ca²⁺ signaling, JPH2 plays a key role in the development and stability of myocyte ultrastructure.

2. Beavers D.L., et al. Emerging roles of junctophilin-2 in the heart and implications for cardiac diseases. Cardiovascular Research. 2014, 103(2):198-205. PubMed ID: 24935431
   
   

   This article indicates that 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.

3. Guo A., et al. Molecular Determinants of Calpain-dependent Cleavage of Junctophilin-2 Protein in Cardiomyocytes. The Journal of Biological Chemistry. 2015, 290(29):17946-17955. PubMed ID: 26063807
   
   

   The results of this article demonstrate that exogenous expression of putative JPH2 cleavage fragments was not sufficient to rescue Ca²⁺ handling in JPH2-deficient cardiomyocytes, indicating that cleaved JPH2 is non-functional for normal Ca²⁺-induced Ca²⁺ release. This article provides new molecular insights into the posttranslational regulatory mechanisms of JPH2 in cardiac diseases.

4. Wu C.Y.C., et al. Calpain‐Dependent Cleavage of Junctophilin‐2 and T‐Tubule Remodeling in a Mouse Model of Reversible Heart Failure. Journal of the American Heart Association: Cardiovascular and Cerebrovascular Disease. 2014, 3(3):e000527. PubMed ID: 24958777
   
   

   Authors in this article apply a mouse model of reversible heart failure to prove that the treatment of mice with a calpain inhibitor prevented Gαq-dependent JPH2 cleavage, T-tubule disruption, and the development of heart failure.

5. Fan H.K., et al. Functional interaction of Junctophilin 2 with small- conductance Ca2+-activated potassium channel subtype 2(SK2) in mouse cardiac myocytes. Acta Physiologica. 2017, 222(3):e12986. PubMed ID: 29055091
   
   

   The data presented in this article provide evidence that the functional interaction between JHP2 and SK2 channels is present in the native mouse heart tissue. JHP2, as junctional membrane complex (JMC) protein, is an important regulator of the cardiac SK channels.

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Reference

1. Landstrom A P., et al. (2014) The junctophilin family of proteins: From bench to bedside. Trends Mol. Med. 20(6):353-362.

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