# Voltage-gated sodium channels in lysosomal physiology

> **NIH NIH R01** · UNIVERSITY OF PENNSYLVANIA · 2021 · $490,439

## Abstract

The biophysical properties and the regulation of plasma membranes have been extensively studied for several
decades. Hundreds of ion channels have been discovered. They regulate essentially every aspect of cell
biology and physiological functions, ranging from muscle contraction and neuronal signaling to hormone
secretion and gene expression. In contrast, the biophysical properties of intracellular organelle membranes
have been much less investigated. In this propose, we extend our preliminary studies of lysosomal
membranes, with focus on lysosomal sodium channels. Lysosomes are the digestion and recycling center in
mammalian cells. They play central roles in cellular clearance, nutrient recycling, energy generation and
signaling. Dysfunction of lysosomes leads to severe diseases such as lysosomal storage diseases and
neurodegenerative diseases including Parkinson’s and Alzheimer’s. Recent electrophysiological recordings,
molecular cloning, protein chemistry and mouse genetics studies have started to define the properties of
lysosomal membranes. Whole-lysosome current-clamp recording has discovered that a subset of lysosomes
generate action potential-like membrane depolarization spikes. The ability to generate spikes is critically
dependent on a novel voltage-gated sodium-permeable channel formed by the two-pore repeat channel 1
(TPC1) protein. In addition, preliminary studies suggest that TPC channels are coupled to the metabolic state
and nutrient availability of the cell, and to the luminal pH of the organelle. We propose three specific aims to
expand our studies. Patch clamp recordings will be used to test the hypothesis that lysosomal excitability is
widely expressed and can be found in both excitable and non-excitable cells. Whether the excitability is
regulated by metabolic state and the availability of nutrients will also be tested (Aim 1). TPC channels are
controlled by cytosolic ATP concentration via the mTOR kinase. We will use biochemical approaches to define
the mechanisms underlying the channel’s ATP sensitivity (Aim 2). TPC channels are generally selective for
sodium, and evidences suggest that the channels are also calcium-permeable. In Aim 3, biochemical and
electrophysiological experiments will be performed to define the channel permeation and its regulation by
calcium (Aim 3). Given the physiological importance of lysosomes, the proposed studies will help fill the
knowledge gap in our understanding of the properties of lysosomal membranes and their functions under
normal and pathological states such as neurodegenerative diseases.

## Key facts

- **NIH application ID:** 10127693
- **Project number:** 5R01HL147379-03
- **Recipient organization:** UNIVERSITY OF PENNSYLVANIA
- **Principal Investigator:** Dejian Ren
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $490,439
- **Award type:** 5
- **Project period:** 2019-04-15 → 2023-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10127693

## Citation

> US National Institutes of Health, RePORTER application 10127693, Voltage-gated sodium channels in lysosomal physiology (5R01HL147379-03). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10127693. Licensed CC0.

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