JSRP1

JSRP1 (JP-45) is an integral membrane protein of the skeletal muscle sarcoplasmic reticulum junctional face membrane that functions as a regulator of excitation-contraction coupling (PMID:12871958, PMID:16638807). Tissue-selective and localized to the SR junctional face membrane, it co-localizes with the ryanodine receptor and forms a complex with the Cav1.1 (DHPR) alpha1.1 subunit and calsequestrin (PMID:11023841, PMID:12871958). Its cytoplasmic domain (residues 1–80) binds two distinct Cav1.1 regions—the I-II loop and the C-terminus—and also engages the Cav1 beta1a subunit, which competes for the I-II loop interaction site (PMID:16638807). Through these interactions JP-45 is required for functional expression and voltage sensing of Cav1.1, modulating charge movement and the coupling between the DHPR voltage sensor and SR Ca2+ release rather than altering SR Ca2+ content (PMID:16638807, PMID:16423849). Two human missense variants (P108L, G150A) reduce DHPR sensitivity to activation during EC coupling (PMID:22927026).

1. 2000 Medium

   Establishing that a previously uncharacterized 45 kDa protein is a tissue-selective resident of the SR junctional face membrane defined where it could act in muscle.

   Evidence Subcellular fractionation, immunoprecipitation and in vitro PKA phosphorylation of microsomes from multiple tissues

   PMID:11023841

   Open questions at the time

   • Binding partners not yet identified
   • Functional role in EC coupling not established
   • Physiological relevance of PKA phosphorylation untested
2. 2003 High

   Identifying JP-45's molecular partners answered whether it is positioned to participate in the DHPR-RyR coupling machinery.

   Evidence cDNA cloning, double immunofluorescence and reciprocal co-immunoprecipitation in skeletal muscle SR

   PMID:12871958

   Open questions at the time

   • Interaction interfaces not mapped
   • Functional consequence of the interactions untested
   • Direct vs indirect association within the complex unresolved
3. 2006 High

   Mapping the cytoplasmic domain interactions and combining with gain/loss-of-function established that JP-45 is required for functional expression and voltage sensing of Cav1.1.

   Evidence Domain pulldown mapping plus overexpression and siRNA depletion in C2C12 myotubes with whole-cell charge-movement recording

   PMID:16638807

   Open questions at the time

   • Stoichiometry of the JP-45/Cav1.1/beta1a complex unresolved
   • Mechanism by which beta1a competition is regulated in vivo unclear
4. 2006 Medium

   Quantitative Ca2+ flux analysis distinguished whether JP-45 acts on SR Ca2+ load versus the voltage-sensor-to-release coupling step.

   Evidence Nuclear microinjection overexpression in C2C12 myotubes with voltage-clamp, fura-2 imaging and Ca2+ flux modeling

   PMID:16423849

   Open questions at the time

   • Overexpression only, no loss-of-function confirmation
   • Molecular step in DHPR-RyR coupling affected not pinpointed
5. 2012 Medium

   Testing human JSRP1 variants asked whether sequence variation in JP-45 alters EC coupling and disease modulation.

   Evidence Population genotyping and functional EC coupling assays in muscle cells expressing P108L and G150A variants

   PMID:22927026

   Open questions at the time

   • Variants not enriched in malignant hyperthermia cohorts
   • Structural basis of reduced DHPR sensitivity not defined
   • Interaction with RYR1 mutations inferred, not directly demonstrated

• The structural basis of JP-45's regulation of Cav1.1 voltage sensing and how beta1a competition is dynamically controlled during EC coupling remain unresolved.
• No structural model of the JP-45/Cav1.1 interface
• In vivo regulatory role of PKA phosphorylation unknown
• Whole-animal phenotype of JSRP1 loss not characterized in the corpus