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Two pore channel protein 2

Definition:

Intracellular channel initially characterized as a non-selective Ca(2+)-permeable channel activated by NAADP (nicotinic acid adenine dinucleotide phosphate), it is also a highly-selective Na(+) channel activated directly by PI(3,5)P2 (phosphatidylinositol 3,5-bisphosphate). Localizes to the lysosomal and late endosome membranes where it regulates organellar membrane excitability, membrane trafficking, and pH homeostasis. Is associated with a plethora of physiological processes, including mTOR-dependent nutrient sensing, skin pigmentation and autophagy. Ion selectivity is not fixed but rather agonist-dependent and under defined ionic conditions, can be readily activated by both NAADP and PI(3,5)P2. As calcium channel, it increases the pH in the lysosomal lumen, as sodium channel, it promotes lysosomal exocytosis. Plays a crucial role in endolysosomal trafficking in the endolysosomal degradation pathway and is potentially involved in the homeostatic control of many macromolecules and cell metabolites (By similarity). Also expressed in melanosomes of pigmented cells where mediates a Ca(2+) channel and/or PI(3,5)P2-activated melanosomal Na(+) channel to acidify pH and inhibit tyrosinase activity required for melanogenesis and pigmentation. Unlike the voltage-dependent TPCN1, TPCN2 is voltage independent and can be activated solely by PI(3,5)P2 binding. In contrast, PI(4,5)P2, PI(3,4)P2, PI(3)P and PI(5)P have no obvious effect on channel activation.; (Microbial infection) During Ebola virus (EBOV) infection, controls the movement of endosomes containing virus particles and is required by EBOV to escape from the endosomal network into the cell cytoplasm.; (Microbial infection) Required for cell entry of coronaviruses SARS-CoV and SARS-CoV-2, as well as human coronavirus EMC (HCoV-EMC), by endocytosis.

References:

[1]. Ji She, et al. Structural mechanisms of phospholipid activation of the human TPC2 channel. Elife. 2019 Mar 12;8:e45222. [Content Brief]

[2]. Patrick Sulem, et al. Two newly identified genetic determinants of pigmentation in Europeans. Nat Genet. 2008 Jul;40(7):835-7. [Content Brief]

[3]. Xiaoli Zhang, et al. Agonist-specific voltage-dependent gating of lysosomal two-pore Na+ channels. Elife. 2019 Dec 11;8:e51423. [Content Brief]

[4]. Chunlei Cang, et al. The voltage-gated sodium channel TPC1 confers endolysosomal excitability. Nat Chem Biol. 2014 Jun;10(6):463-9. [Content Brief]

[5]. Xuhui Jin, et al. Targeting Two-Pore Channels: Current Progress and Future Challenges. Trends Pharmacol Sci. 2020 Aug;41(8):582-594. [Content Brief]

[6]. Peter J Calcraft, et al. NAADP mobilizes calcium from acidic organelles through two-pore channels. Nature. 2009 May 28;459(7246):596-600. [Content Brief]

[7]. Eugen Brailoiu, et al. Essential requirement for two-pore channel 1 in NAADP-mediated calcium signaling. J Cell Biol. 2009 Jul 27;186(2):201-9. [Content Brief]

[8]. Andrea L Ambrosio, et al. TPC2 controls pigmentation by regulating melanosome pH and size. Proc Natl Acad Sci U S A. 2016 May 17;113(20):5622-7. [Content Brief]

[9]. Chunlei Cang, et al. mTOR regulates lysosomal ATP-sensitive two-pore Na(+) channels to adapt to metabolic state. Cell. 2013 Feb 14;152(4):778-790. [Content Brief]

[10]. Susanne Gerndt, et al. Agonist-mediated switching of ion selectivity in TPC2 differentially promotes lysosomal function. Elife. 2020 Mar 16;9:e54712. [Content Brief]

[11]. Xiang Wang, et al. TPC proteins are phosphoinositide- activated sodium-selective ion channels in endosomes and lysosomes. Cell. 2012 Oct 12;151(2):372-83. [Content Brief]

[12]. Xiuyuan Ou, et al. Characterization of spike glycoprotein of SARS-CoV-2 on virus entry and its immune cross-reactivity with SARS-CoV. Nat Commun. 2020 Mar 27;11(1):1620. [Content Brief]

[13]. Archana Jha, et al. Convergent regulation of the lysosomal two-pore channel-2 by Mg²⁺, NAADP, PI(3,5)P₂ and multiple protein kinases. EMBO J. 2014 Mar 3;33(5):501-11. [Content Brief]

[14]. Yasuteru Sakurai, et al. Ebola virus. Two-pore channels control Ebola virus host cell entry and are drug targets for disease treatment. Science. 2015 Feb 27;347(6225):995-8. [Content Brief]

[15]. Eugen Brailoiu, et al. An NAADP-gated two-pore channel targeted to the plasma membrane uncouples triggering from amplifying Ca2+ signals. J Biol Chem. 2010 Dec 3;285(49):38511-6. [Content Brief]

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