# Molecular basis of the NAADP-gated calcium release channel complexes

> **NIH NIH R01** · UNIVERSITY OF TX MD ANDERSON CAN CTR · 2022 · $332,100

## Abstract

Project Summary:
 Intracellular Ca2+ signaling via changes in cytosolic Ca2+ concentration controls a wide range of cellular
and physiologic processes. Ca2+ mobilization from intracellular stores mediated by second messengers plays a
critical role in regulation of cytosolic Ca2+ levels. Nicotinic acid adenine dinucleotide phosphate (NAADP) is the
most potent Ca2+-mobilizing second messenger identified to date; it uniquely mobilizes Ca2+ from acidic
endolysosomal organelles. NAADP has been shown to be effective in evoking Ca2+ release in a multitude of
different mammalian cells and defects in NAADP signaling are now being implicated in many diseases. Despite
the importance of NAADP-evoked Ca2+ signaling, the molecular basis of NAADP-evoked Ca2+ release remains
largely unclear. With immobilized NAADP–based affinity purification and quantitative proteomic analyses of
NAADP and TPC interacting proteins, we identified Lsm12 to be a shared interacting partner of NAADP, TPC1,
and TPC2. Lsm12 directly binds to NAADP via its Lsm domain, colocalizes with TPC2, and mediates the
apparent association of NAADP to isolated TPC2 or TPC2-containing membranes. Lsm12 is essential and
immediately participates in NAADP-evoked TPC activation and Ca2+ mobilization. Our findings thus reveal a
putative RNA-binding protein functioning as an NAADP receptor and a TPC regulatory protein and provide a
new molecular basis for understanding the mechanisms of NAADP signaling. Our further studies showed that
Lsm12 has multifaceted function by affecting TPC channel gating properties and functioning in non-TPC
dependent NAADP signaling. We hypothesize that: 1) Lsm12 as an NAADP receptor achieves its high
selectivity and affinity to NAADP than NADP via its Lsm domain; 2) Lsm12 mediates TPC channel activation by
NAADP via protein-protein interactions and/or dephosphorylation; and 3) Lsm12 can regulate multiple ion
channels and mediate NAADP-evoked intracellular Ca2+ elevation via shared mechanisms. To test our
hypotheses, we will pursue the following 3 specific aims. Aim 1. Determine the molecular mechanism of the
Lsm domain in NAADP binding. Aim 2. Determine the molecular mechanisms of Lsm12-mediated TPC
activation by NAADP. Aim 3. Determine the multifaceted function of Lsm12 in NAADP-evoked Ca2+ signaling.
Findings from the proposed research will elucidate the molecular mechanisms and function of NAADP/Lsm12-
mediated Ca2+ signaling and facilitate the development of new drugs for this important Ca2+ signaling process.

## Key facts

- **NIH application ID:** 10445514
- **Project number:** 2R01GM130814-05
- **Recipient organization:** UNIVERSITY OF TX MD ANDERSON CAN CTR
- **Principal Investigator:** Jiusheng Yan
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $332,100
- **Award type:** 2
- **Project period:** 2018-09-15 → 2026-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10445514

## Citation

> US National Institutes of Health, RePORTER application 10445514, Molecular basis of the NAADP-gated calcium release channel complexes (2R01GM130814-05). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10445514. Licensed CC0.

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