# Regulation of lysosomal potassium channels

> **NIH NIH R01** · UNIVERSITY OF PENNSYLVANIA · 2021 · $325,837

## Abstract

Program Director/Principal Investigator (Last, First, Middle): Ren, Dejian
The overall goal of the proposed research is to understand the function and the regulation of potassium ion
channels to the function of lysosomes. Potassium is the most abundant intracellular ion that faces both plasma
membrane and organelle membrane. Plasma membranes are highly permeable to potassium. More than 80
potassium channels have now been discovered to mediate such plasma membrane potassium permeability. In
contrast, how potassium passes intracellular organelles such as lysosomes is much less understood.
Lysosomes play fundamental roles in cellular clearance, digestion, recycling, exocytosis and membrane repair.
Because of high concentration of calcium in the lumen, lysosomes are also calcium stores from which calcium
is released into cytosol to shape cytosolic calcium kinetics and to regulate muscle contraction and hormone
secretion. Lysosomal dysfunction has been linked to pathophysiological conditions such as lysosomal storage
diseases, cancer and neurodegeneration. Therefore understanding how lysosomal membrane mediates ionic
permeability is important to our understanding of the organelle’s physiology function. We recently discovered a
novel protein TMEM175 that forms a potassium-selective channel in lysosomal membrane. Genetic variation
in human TMEM175 is also implicated in Parkinson’s disease. We propose three specific aims to expand our
preliminary findings. In Aim 1, we will use patch clamp recordings to compare wild-type and TMEM175
knockout animals and will test whether there are other major lysosomal potassium channels in addition to
TMEM175. Unlike those of plasma membrane channels, the functions of lysosomal potassium channels are
largely unknown. In Aim 2, we will use the TMEM175 knockout mouse model to test the hypothesis that
potassium channels regulate the normal working of lysosomes including organelle membrane potential
regulation, luminal acidification, vesicle fusion and autophagy. In Aim 3, we will test whether TMEM175, like
many other potassium channels on plasma membrane, is regulated by protein kinases. Using protein
chemistry experiments, we will also determine the structural requirements for such regulation. Because of the
fundamental function of lysosomes, the studies will reveal how lysosomal potassium channels contribute to the
organelle’s function under physiological and pathological conditions.
OMB No. 0925-0001/0002 (Rev. 01/18 Approved Through 03/31/2020) Page

## Key facts

- **NIH application ID:** 10146424
- **Project number:** 5R01GM133172-03
- **Recipient organization:** UNIVERSITY OF PENNSYLVANIA
- **Principal Investigator:** Dejian Ren
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $325,837
- **Award type:** 5
- **Project period:** 2019-04-01 → 2023-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10146424

## Citation

> US National Institutes of Health, RePORTER application 10146424, Regulation of lysosomal potassium channels (5R01GM133172-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10146424. Licensed CC0.

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