Junctophilin 1 (JP1; JPH1) of 661 aas and 1 C-terminal TMS.  Essential for Ca²⁺ signaling in skeletal muscle (Nakada et al. 2018) because JPs recruit L-type calcium channels to the junctional membrane through physical interaction, and they ensure robust excitation-contraction coupling at triads in skeletal muscle. In Human there are 4 junctophilins, all similar in sequence, all containing MORN repeats.

JP1 of Homo sapiens

Uncharacterized MORN repeat-containing protein 1 of 364 aas and one C-terminal TMS.

UP of Plasmodium malariae

MORN repeat containing protein of 850 aas and 0 TMSs.

MORN repeat protein of Candidatus Magnetobacterium bavaricum

Junctophilin-2, JPH2 or JP2, of 696 aas and 2 TMSs, N- and C-terminal. It is a structural membrane protein that tethers T-tubules to the sarcoplasmic reticulum to allow coordinated calcium-induced calcium release in cardiomyocytes (Chan et al. 2019). Defective excitation-contraction coupling in myocardial ischemia-reperfusion (IR) injury is associated with junctophilin-2 proteolysis. Matrix metalloproteinase-2 (MMP-2) is a zinc and calcium-dependent protease that is activated by oxidative stress in myocardial IR injury and cleaves both intracellular and extracellular substrates. Junctophilin-2 is targeted by MMP-2, an MMP inhibitor, ARP-100, was used. IR injury impaired the recovery of cardiac contractile function which was associated with increased degradation of junctophilin-2 and damaged cardiac dyads. In IR hearts, ARP-100 improved the recovery of cardiac contractile function, attenuated junctophilin-2 proteolysis, and prevented ultrastructural damage to the dyad. MMP-2 was co-localized with junctophilin-2 in aerobic and IR hearts by immunoprecipitation and immunohistochemistry. In situ zymography showed that MMP activity was localized to the Z-disc and sarcomere in aerobic hearts and accumulated at sites where the striated JPH-2 staining was disrupted in IR hearts. In vitro proteolysis assays showed that junctophilin-2 is susceptible to proteolysis by MMP-2 with multiple MMP-2 cleavage sites between the membrane occupation and recognition nexus repeats and within the divergent region of junctophilin-2. Degradation of junctophilin-2 by MMP-2 is an early consequence of myocardial IR injury which may initiate a cascade of sequelae leading to impaired contractile function (Chan et al. 2019). S-Palmitoylation of junctophilin-2 is critical for its role in tethering the sarcoplasmic reticulum to the plasma membrane (Jiang et al. 2019).

JPH2 of Homo sapiens

Junctophilin-3, JPH3; JP3, of 748 aas and possibly 2 TMSs, one potential TMS near the N-terminus, and one certain TMS at the C-terminus.  Junctophilins contribute to the formation of junctional membrane complexes (JMCs) which link the plasma membrane with the endoplasmic or sarcoplasmic reticulum in excitable cells. It provides a structural foundation for functional cross-talk between the cell surface and intracellular calcium release channels. JPH3 is brain-specific and appears to have an active role in certain neurons involved in motor coordination and memory. JPH4 (Q96JJ6) is also brain-specific and appears to play an active role in certain neurons involved in motor coordination and memory. However, it facilitates inflammatory signalling at plasma membrane-endoplasmic reticulum junctions in sensory neurons(Hogea et al. 2021). JPH3 and JPH4 proteins maintain a Cav1-RyR2-KCa3.1 complex that allows two calcium sources to act in tandem to define the activation properties of KCa3.1 channels and the IsAHP (Sahu et al. 2019).

JPH3 of Homo sapiens

Junctophilin, JPH or JP, of 1054 aas and one C-terminal TMS and possibly one more at about residue 750.  It is functionally equivalent to its four mammalian counterparts and is a modifier of a Huntingtin poly-Q expansion and the Notch pathway (Calpena et al. 2018).

JPH of Drosophila melanogaster (Fruit fly)