JPH4 Membrane Protein Introduction

Introduction of JPH4

JPH4 is encoded by JPH4, JPHL1 or KIAA1831 gene and is also known as Junctophilin-4, JP-4 and Junctophilin-like 1 protein. It belongs to the junctophilin family, which consists of four genes (JP1, JP2, JP3, and JP4) and are expressed in a tissue-specific manner and are known to form ER–PM junctions in excitable cells. JP4 is located at the ER–PM junctions in T cells, where it plays an essential role in both ER Ca²⁺ refilling as well as SOCE, primarily mediated by its interaction with stromal interaction molecule 1.

Function of JPH4 Membrane Protein

JPH4 plays an important role in ER Ca²⁺ Homeostasis and store-operated Ca²⁺ entry in T Cells. Silencing or genetic manipulation of JPH4 decreased ER Ca²⁺ content and store-operated Ca²⁺ entry in T cells, impaired activation of the nuclear factor of activated T cells (NFAT) and extracellular signaling-related kinase (ERK) signaling pathways, and diminished expression of activation markers and cytokines. Mechanistically, JP4 directly interacted with stromal interaction molecule 1 via its cytoplasmic domain and facilitated its recruitment into the junctions. Accordingly, expression of this cytoplasmic fragment of JPH4 inhibited store-operated Ca²⁺ entry. Furthermore, JPH4 also formed a complex with junctate, a Ca²⁺-sensing ER-resident protein, previously shown to mediate stromal interaction molecule 1 recruitment into the junctions. The junctate–JPH4 complex located at the junctions cooperatively interacts with stromal interaction molecule 1 to maintain ER Ca²⁺ homeostasis and mediate store-operated Ca²⁺ entry in T cells. Another possible role of JPH4 can be its involvement in the ER stress pathways because JPH4 controls ER Ca²⁺ Homeostasis and ER stress activates Ca²⁺ and lipid signaling.

Fig .1 Signaling pathway of JPH4 (JP4) in ER–PM junctions (Woo JS., et al. 2016).

Application of JPH4 Membrane Protein in Literature

1. Woo JS., et al. Junctophilin-4, a component of the endoplasmic reticulum–plasma membrane junctions, regulates Ca²⁺ dynamics in T cells. Proceedings of the National Academy of Sciences of the United States of America. 2016, 113(10):2762-2767. PubMed ID: 26929330
   
   

   The results of this article uncover an unexpected role of JPh4 in ER Ca²⁺ homeostasis and Ca²⁺ signaling in T cells. Mechanistically, JPh4 interacts with junctate to form a protein complex at the ER–PM junctions to recruit STIM1 by direct protein interaction.

2. Landstrom AP., et al. The junctophilin family of proteins: From bench to bedside. Trends Mol. Med. 2014, 20(6):353-362. PubMed ID: 24636942
   
   

   This article reports that JPH3/4 double knock-out mice demonstrate disrupted intracellular Ca²⁺ signaling via the N-methyl D-aspartate (NMDA) glutamate receptors and intracellular neuronal RyRs as well as the small-conductance Ca²⁺-activated potassium (SK) channels.

3. Nishi M., et al. Coexpression of junctophilin type 3 and type 4 in brain. Mol. Brain Res. 2003, 118(1):102-110. PubMed ID: 14559359
   
   

   Authors in this article perform in situ hybridization analysis which reveals that both JPH-3 and JPH-4 mRNAs are expressed in discrete neuronal sites, and their overall regional distribution patterns were similar in the brain.

4. Moriguchi S., et al. Functional uncoupling between Ca(2+) release and afterhyperpolarization in mutant hippocampal neurons lacking junctophilins. Proceedings of the National Academy of Sciences of the United States of America. 2006, 103(28):10811-10816. PubMed ID: 16809425
   
   

   Author in this article use knockout mice lacking both JPH-3 and JPH-4 (JP-DKO mice) to demonstrate their essential contributions to the tuning of excitability and plasticity in hippocampal pyramidal neurons.

5. Kakizawa S., et al. Functional Crosstalk Between Cell-Surface and Intracellular Channels Mediated by Junctophilins Essential for Neuronal Functions. The Cerebellum. 2008, 7(3):385-391. PubMed ID: 8607668
   
   

   This article proves that JPH3 and JPH4 are coexpressed in all neuronal sites in the central nervous system and double-knockout mice lacking both JPH3 and JPH4 show impaired performance in the Y-maze and passive avoidance tests, indicating abnormal hippocampal functions.

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Reference

1. Woo JS., et al. (2016) Junctophilin-4, a component of the endoplasmic reticulum–plasma membrane junctions, regulates Ca²⁺ dynamics in T cells. Proceedings of the National Academy of Sciences of the United States of America. 113(10):2762-2767.

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