# Molecular physiology of CALHM ion channels

> **NIH NIH R01** · UNIVERSITY OF PENNSYLVANIA · 2020 · $524,514

## Abstract

The broad goal of our proposed studies is to exploit our new insights into the molecular mechanisms and
physiological roles of CALHM1 and CALHM3 as components of a novel ion channel in taste perception. We
discovered CALHM1 as a membrane protein that expressed throughout the brain and in taste buds that lacks
significant homology to other proteins, although five homologs have been identified, and CALHM1 is
conserved across species. We identified CALHM1 as a pore-forming subunit of an ion channel with a large
pore diameter and gating regulation by voltage and extracellular Ca2+ (Ca2+o). We discovered that CALHM1 is
essential for perceptions of sweet, bitter and umami tastes by type II taste bud cells, since CALHM1-knockout
mice cannot perceive these tastants. We identified the essential role of CALHM1 by discovering that it is a
voltage-gated ATP-permeable ion channel, and that tastant-evoked Na+ action potentials trigger ATP release
as a neurotransmitter through CALHM1-associated channels to transduce taste information from the periphery
to the central nervous system. We further discovered that CALHM3 is an essential component of the native
voltage-gated ATP-release channel, contributing as a pore-forming subunit with CALHM1 to create a
heteromeric ATP-release channel in type II cells. Genetic deletion of CALHM3 also eliminates the ability of
mice to perceive sweet, bitter and umami substances. The molecular mechanisms and structural bases of ion
permeation and gating of CALHM channels are not understood despite their physiological importance. Nor is it
understood how integration of CALHM3 into a CALHM1/3 channel so strongly affects voltage-gated activation,
a key feature that allows CALHM1/3 channels to respond to action potentials. Temperature notably influences
taste perception with physiological and hedonistic implications, but the contribution of peripheral taste-transduction mechanisms to the effects of temperature on the perception and sensation of tastes is largely
unknown. We have discovered that temperature strikingly influences CALHM1/3 conductance as well as the
electrical excitability of type II cells. We will employ electrophysiology in native taste bud cells and
heterologous expression systems, mutagenesis, cryo-EM, and modeling to define the gating mechanisms of
CALHM1 and CALHM1/3 channels, how CALHM3 as a pore-forming subunit enhances voltage-gated
activation of CALHM1/3 channels, and how CALHM1/3 channels respond to action potentials evoked by
tastant stimulation over a wide range of temperatures. Using a novel mouse model in which CALHM1/3 in
taste bud cells has been engineered to have distinct temperature sensitivity, we will define how differential
effects of temperature on ATP-release channel gating and excitability may provide a mechanism for how a
temperature-sensitive channel in the peripheral gustatory system contributes to the influence of temperature
on taste sensitivity and perception.

## Key facts

- **NIH application ID:** 10049352
- **Project number:** 1R01DC018278-01A1
- **Recipient organization:** UNIVERSITY OF PENNSYLVANIA
- **Principal Investigator:** James Kevin FOSKETT
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $524,514
- **Award type:** 1
- **Project period:** 2020-07-01 → 2025-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10049352

## Citation

> US National Institutes of Health, RePORTER application 10049352, Molecular physiology of CALHM ion channels (1R01DC018278-01A1). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10049352. Licensed CC0.

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