JPH1

JPH1 (junctophilin-1) is a structural membrane-tethering protein that physically bridges the sarcoplasmic reticulum (SR) and T-tubule plasma membrane to form junctional membrane complexes essential for excitation–contraction (EC) coupling in skeletal muscle (PMID:10949023). Its C-terminal hydrophobic segment anchors in the SR membrane while its cytoplasmic domain binds the T-tubule; this domain also directly interacts with the RyR1 Ca²⁺-release channel in a conformation- and redox-sensitive manner through hyper-reactive cysteine residues (Cys101, Cys402, Cys627) (PMID:17237236). JPH1 is subject to Ca²⁺-dependent proteolysis by µ-calpain near its C-terminus, which disrupts EC coupling and is observed in dystrophic muscle (PMID:23148318). Homozygous loss-of-function variants in JPH1 cause congenital myopathy with defective triad junction formation in humans (PMID:39209426).

1. 2000 High

   The identification of junctophilins as a protein family established that a dedicated structural molecule tethers the SR to T-tubules, answering how junctional membrane complexes critical for EC coupling are physically maintained.

   Evidence Molecular cloning, subcellular fractionation, and JP-2-null mouse analysis demonstrating loss of junctional membrane complexes

   PMID:10949023

   Open questions at the time

   • No direct JPH1 knockout phenotype characterized at this stage
   • Identity of JPH1's channel interaction partners unknown
   • Mechanism of plasma membrane binding by the cytoplasmic domain unresolved
2. 2007 High

   Demonstrating a direct, conformation-sensitive JPH1–RyR1 interaction with redox-sensitive cysteines revealed that JPH1 is not merely a passive tether but an integral component of the Ca²⁺-release channel complex capable of sensing oxidative stress.

   Evidence Co-immunoprecipitation and mass spectrometry–based cysteine mapping with thiol-reactive probes in skeletal muscle preparations

   PMID:17237236

   Open questions at the time

   • Functional consequences of cysteine oxidation on EC coupling not directly measured
   • No structural model of the JPH1–RyR1 interface
   • Whether redox modification of JPH1 occurs in vivo under physiological or pathological conditions was not tested
3. 2012 High

   Identification of µ-calpain–mediated proteolysis of JPH1 at pathological Ca²⁺ levels, coincident with loss of depolarization-induced force, established a molecular mechanism by which Ca²⁺ overload dismantles the triad junction and disables EC coupling.

   Evidence Biochemical fractionation at defined [Ca²⁺], skinned fibre force measurements, in vitro stimulation, and immunoblotting in wild-type and mdx mouse muscle

   PMID:23148318

   Open questions at the time

   • Exact calpain cleavage site(s) in JPH1 not mapped at residue resolution
   • Whether the released ~75 kDa fragment has any signaling role (as reported for JPH2 N-terminal fragments) is unknown
   • Contribution of JPH1 proteolysis versus other calpain substrates to EC coupling failure not dissected
4. 2024 Medium

   Discovery of biallelic JPH1 loss-of-function variants causing human congenital myopathy with triad abnormalities demonstrated that JPH1 is non-redundant with JPH2 in skeletal muscle and is required for normal triad formation in humans.

   Evidence Exome/genome sequencing in four unrelated families, RNA-seq expression outlier analysis, and electron microscopy of patient muscle biopsies

   PMID:39209426

   Open questions at the time

   • Single study; independent replication in additional cohorts not yet available
   • Genotype–phenotype correlations across different JPH1 variant types not established
   • Whether residual JPH2 partially compensates in affected patients is uncharacterized

• Key unresolved questions include the atomic-resolution structure of JPH1 (alone and in complex with RyR1), the precise calpain cleavage site(s), the in vivo functional consequences of JPH1 cysteine oxidation, and whether the proteolytic N-terminal fragment has nuclear or signaling roles analogous to those described for JPH2.
• No high-resolution structure of any junctophilin-1 domain or complex
• Potential nuclear translocation of cleavage fragments untested for JPH1
• Therapeutic strategies to prevent JPH1 proteolysis in dystrophic or overloaded muscle not explored