# Molecular Mechanisms of lon Channels in T Lymphocytes

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA-IRVINE · 2021 · $550,028

## Abstract

Project Summary / Abstract
Store-operated Ca2+ entry (SOCE) underlies numerous cellular processes throughout the body and initiates
signaling cascades in T lymphocytes that cause changes in motility, secretion of cytolytic granules, cytokine
release, and cell proliferation. The channels that underlie SOCE have been identified recently through RNA
interference (RNAi) screening as a conserved family of four transmembrane-spanning proteins named Orai that
are activated by STIM proteins in the ER membrane. Isoforms of these proteins are expressed throughout the body
in a tissue-specific manner. Important cellular functions of Orai1 have been identified in lymphocytes, microglia,
mast cells, blood platelets, sweat and salivary glands, dentition, vascular smooth muscle, endothelial cells, skeletal
muscle, microglia, astrocytes, and neurons. In the immune system, STIM1 and Orai1 mediate antigen-induced
Ca2+ signaling, motility inhibition at the site of antigen presentation, secretion of cytolytic granules by CD8+ T cells
and NK cells, and gene expression responses that lead to cytokine release and cell proliferation. STIM and Orai
proteins are being developed as targets for treatment of autoimmune diseases and prevention of transplant
rejection. Our overall goal is to understand how Orai channels function at the molecular and cellular level.
Orai channels in the plasma membrane are unrelated to other known ion channels and have unusual
characteristics that distinguish them, including a very high degree of selectivity for Ca2+, low single-channel
conductance, and activation by binding of a small cytosolic domain of the STIM protein. Moreover, the human Orai1
and Orai3 proteins differ in their activation requirements and tissue distribution. In this project, we have three goals.
We seek to understand at molecular, subcellular, and cellular levels: 1) how Orai1 is activated by STIM1 at the
single-channel level; 2) how Orai1 signals locally in puncta to generate localized Ca2+ signals; 3) how local Ca2+
signals modulate T cell motility, turning behavior and stopping during immune surveillance. To accomplish these
Aims, we have developed and continue to develop new tools for monitoring local Ca2+ signals that will be broadly
applicable. Our studies will include electrophysiological analysis, optical imaging of Ca2+ flux through Orai1
channels, and two-photon imaging of in situ cellular motility. Overall, our project will provide fundamental insights
into the Orai1 proteins that are currently being targeted for treatment of autoimmune disorders, chronic
inflammatory conditions, and neurodegerative diseases such as Alzheimer’s.

## Key facts

- **NIH application ID:** 10168652
- **Project number:** 5R01NS014609-41
- **Recipient organization:** UNIVERSITY OF CALIFORNIA-IRVINE
- **Principal Investigator:** MICHAEL D CAHALAN
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $550,028
- **Award type:** 5
- **Project period:** 1978-09-15 → 2023-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10168652

## Citation

> US National Institutes of Health, RePORTER application 10168652, Molecular Mechanisms of lon Channels in T Lymphocytes (5R01NS014609-41). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10168652. Licensed CC0.

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