TPC2 Is a Novel NAADP-sensitive Ca2+ Release Channel, Operating as a Dual Sensor of Luminal pH and Ca2+ | Semantic Scholar (2024)

The concerted regulation of TPC1 activity by luminal Ca2+ and by membrane potential thus provides a potential mechanism to explain NAADP-induced Ca1+ oscillations and cell function.

NAADP mediates complex Ca2+ interactions between endolysosomes and the sarcoplasmic reticulum to regulate vascular reactivity and other cellular functions to improve the understanding of NAADP-dependent regulation of pulmonary vascular functions.

This work has suggested that intracellular Ca2+ release channels may be closely apposed, possibly at specific membrane contact sites between acidic organelles and the endoplasmic reticulum.

It is proposed that NAADP triggers H+ release from lysosomes and endolysomes through activation of TPC1, but that the Ca2+-releasing ability of T PC1 will depend on the ionic composition of the acidic stores and may be influenced by other regulators that affect TPC 1 ion permeation.

Photolabeling data suggest that an accessory component within a larger TPC complex is responsible for binding NAADP that is unique from the core channel itself, and necessitates critical evaluation of current models of NAadP-triggered activation of the TPC family.

Lsm12 is identified as an NAadP receptor essential for NAADP-evoked Ca2+ release from lysosomes via NAADp binding on its Lsm domain and provides a molecular basis for understanding the mechanisms ofNAADP signaling.

The significantly different gating and ion conducting properties of TPC1 and TPC2 suggest that these two ion channels may play complementary physiological roles as Ca2+‐release channels of the endolysosomal system.

Biophysical analysis in conjunction with site-directed mutagenesis demonstrates that two-pore channels are pore-forming subunits of NAADP-gated ion channels, indicating that TPCs are the likely long sought targets forNAADP.

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TPCN2 is a major component of the long-sought lysosomal NAADP-dependent Ca2+-release channel and displays the basic properties of native NAADP-dependent Ca2+-release channels.

It is shown that two-pore channels (TPCs) comprise a family of NAADP receptors, with human TPC1 and chicken TPCN3 being expressed on endosomal membranes, andhuman TPC2 on lysosome membranes when expressed in HEK293 cells, which will advance the understanding of the physiological role ofNAADP.

The crystal structure of CD38 and the structures of its various substrate complexes have now been determined, clarifying the mechanism of its multifunctional catalysis, and it is anticipated that these advances will lead to the unmasking of all the key components of the Ca2+ signaling pathway mediated by NAADP.

The results of the present study further support acidic stores as targets for NAadP and for the first time reveal an adjunct role for NAADP in regulating the pH(L) of intracellular organelles.

It is described how two-pore channels may also trigger further Ca2+ release by coupling to the endoplasmic reticular stores through activation of IP3 receptors and ryanodine receptors.

It is shown that the previously uncharacterized human two-pore channels (TPC1 and TPC2) are endolysosomal proteins, that NAADP-mediated calcium signals are enhanced by overexpression of T PC1 and attenuated after knockdown of TPC1, and that mutation of a single highly conserved residue within a putative pore region abrogated calcium release byNAADP.

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