{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\n Junctophilin‐4 (JPH4) is emerging as a key structural protein that creates and maintains specialized membrane contact sites between the endoplasmic reticulum (ER) and the plasma membrane (PM), thereby establishing discrete Ca²⁺ signaling microdomains in multiple cell types. In T lymphocytes, for example, JPH4 localizes at the ER‐PM junctions where it directly interacts with the ER Ca²⁺ sensor STIM1 (via its cytoplasmic domain) and with junctate. This interaction facilitates the recruitment of STIM1 into junctional sites, which is critical for maintaining ER Ca²⁺ homeostasis and for efficient store‐operated Ca²⁺ entry that underlies proper T cell activation."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "1"}]}, {"type": "t", "text": ""}]}, {"type": "t", "text": "\n \n "}, {"type": "p", "children": [{"type": "t", "text": "\n In neurons, particularly in hippocampal CA1 pyramidal cells, JPH4, along with JPH3, functions as a molecular tether between the ER and the PM. This positioning is crucial for organizing a tripartite complex that includes voltage‐dependent Ca²⁺ channels (Cav1 subtypes), ryanodine receptors (RyR2), and Ca²⁺-activated K⁺ channels (KCa3.1). Such an arrangement enables the integration of Ca²⁺ influx with Ca²⁺-induced Ca²⁺ release and the consequent activation of K⁺ channels responsible for the slow afterhyperpolarization (sAHP) that modulates neuronal excitability and spike accommodation"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "2"}]}, {"type": "t", "text": ";."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "3"}]}, {"type": "t", "text": "\n "}]}, {"type": "t", "text": "\n \n "}, {"type": "p", "children": [{"type": "t", "text": "\n More broadly, studies of the junctophilin family in excitable cells have underscored the importance of these proteins in coupling surface signals to internal Ca²⁺ release mechanisms. JPH4, as part of this family, contributes to the formation of ER–PM junctions that not only facilitate rapid local Ca²⁺ signaling but also help sustain the dynamics of intracellular Ca²⁺ responses required for diverse functions ranging from immune cell activation to the fine tuning of neuronal firing patterns."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "4"}]}, {"type": "t", "text": "\n "}]}, {"type": "t", "text": "\n \n "}, {"type": "p", "children": [{"type": "t", "text": "\n In summary, JPH4 acts as a critical scaffold that bridges the ER and plasma membrane, ensuring the precise spatial and temporal regulation of Ca²⁺ signals that are essential for both immune function and neuronal excitability.\n "}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Jin Seok Woo, Sonal Srikanth, Miyuki Nishi, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Junctophilin-4, a component of the endoplasmic reticulum-plasma membrane junctions, regulates Ca2+ dynamics in T cells."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Proc Natl Acad Sci U S A (2016)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1073/pnas.1524229113"}], "href": "https://doi.org/10.1073/pnas.1524229113"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "26929330"}], "href": "https://pubmed.ncbi.nlm.nih.gov/26929330"}]}, {"type": "r", "ref": 2, "children": [{"type": "t", "text": "Min Jiang, Junping Hu, Frances K H White, et al. "}, {"type": "b", "children": [{"type": "a", "children": [{"type": "t", "text": "i"}], "href": "i"}, {"type": "t", "text": "S"}, {"type": "a", "children": [{"type": "t", "text": "/i"}], "href": "/i"}, {"type": "t", "text": "-Palmitoylation of junctophilin-2 is critical for its role in tethering the sarcoplasmic reticulum to the plasma membrane."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Biol Chem (2019)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1074/jbc.RA118.006772"}], "href": "https://doi.org/10.1074/jbc.RA118.006772"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "31337710"}], "href": "https://pubmed.ncbi.nlm.nih.gov/31337710"}]}, {"type": "r", "ref": 3, "children": [{"type": "t", "text": "Sho Kakizawa, Yasushi Kishimoto, Kouichi Hashimoto, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Junctophilin-mediated channel crosstalk essential for cerebellar synaptic plasticity."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "EMBO J (2007)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/sj.emboj.7601639"}], "href": "https://doi.org/10.1038/sj.emboj.7601639"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "17347645"}], "href": "https://pubmed.ncbi.nlm.nih.gov/17347645"}]}, {"type": "r", "ref": 4, "children": [{"type": "t", "text": "Eduardo Calpena, Víctor López Del Amo, Mouli Chakraborty, et al. "}, {"type": "b", "children": [{"type": "t", "text": "The "}, {"type": "a", "children": [{"type": "t", "text": "i"}], "href": "i"}, {"type": "t", "text": "Drosophila junctophilin"}, {"type": "a", "children": [{"type": "t", "text": "/i"}], "href": "/i"}, {"type": "t", "text": " gene is functionally equivalent to its four mammalian counterparts and is a modifier of a Huntingtin poly-Q expansion and the Notch pathway."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Dis Model Mech (2018)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1242/dmm.029082"}], "href": "https://doi.org/10.1242/dmm.029082"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "29208631"}], "href": "https://pubmed.ncbi.nlm.nih.gov/29208631"}]}]}]}