1.A.1.11.25
Endosomal/lysosomal, two pore Na⁺and Ca²⁺-release channel  (Na⁺> Ca²⁺) protein of 816 aas and 12 TMSs, TPC1 or TPCN1 (Guo et al. 2017).  Endosomes and lysosomes are electrically excitable organelles (Cang et al. 2014). In a subpopulation of endolysosomes, a brief electrical stimulus elicits a prolonged membrane potential depolarization spike. The organelles have a depolarization-activated, non-inactivating Na⁺ channel (lysoNaV). The channel is formed by a two-repeat six-transmembrane-spanning (2x6 TMS) protein, TPC1, which represents the evolutionary transition between 6 TMS and 4x6 TMS voltage-gated channels. Luminal alkalization also opens lysoNaV by markedly shifting the channel's voltage dependence of activation toward hyperpolarization. Thus, TPC1 is a voltage-gated Na⁺ channel that senses pH changes and confers electrical excitability to organelles (Cang et al. 2014). Essential for Ebola virus (EBOV) host entry.  Several inhibitors act in the nM (tetrandrine) or μM (verapamil; Ned19) range to block Na⁺ and Ca²⁺ channel activity, inhibit virus escape from membrane vesicles and may possibly be used to treat the disease (Sakurai et al. 2015). A cluster of arginine residues in the first domain required for selective voltage-gating of TPC1 map not to the voltage-sensing fourth transmembrane region (S4) but to a cytosolic downstream region (S4-S5 linker). These residues are conserved between TPC isoforms suggesting a generic role in TPC activation. Accordingly, mutation of residues in TPC1 but not the analogous region in the second domain prevents Ca²⁺ release by NAADP in intact cells (Patel et al. 2017). Dramatic conformational changes in the cytoplasmic domains communicate directly with the VSD during activation (Kintzer et al. 2018).  PGRMC1 (the progesterone receptor membrane component1), an ER transmembrane protein that undergoes a unique heme-dependent dimerization, is an interactor of the endosomal two pore channel, TPC1. It regulates ER-endosomal coupling with functional implications for cellular Ca²⁺ dynamics (Gunaratne et al. 2023).  Convergent activation of two-pore channels mediated by the NAADP-binding proteins JPT2 and LSM12 has been reported (Gunaratne et al. 2023).