# Molecular Mechanisms of lon Channels in T Lymphocytes

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA-IRVINE · 2021 · $47,790

## Abstract

Project Summary
The overall objective of this renewal proposal is to better understand how Orai1 channels function in T
cells at the molecular, subcellular, and cellular levels. Orai proteins are a novel class of Ca2+ channels in the
plasma membrane (PM). They are activated by STIM proteins in the ER, with which they colocalize in puncta at
ER-PM junctions following depletion of Ca2+ in the ER lumen. Despite the importance of Orai1 as a potential
therapeutic target in T cells, crucial questions remain at single channel, puncta and cellular levels. In large part this
is because single-channel recording with the patch-clamp technique cannot be applied to Orai1 or other Orai
channels, which have exceptionally low conductance, and because local signalling takes place in STIM1:Orai1
puncta. To circumvent these limitations, our proposal is predicated on our recent development of novel Ca2+-
indicator fusion proteins; an Orai1-GCaMP6f channel-indicator that reports single-channel signals, and a
ratiometric, red/green cytosolic Ca2+ indicator. Implemented in transgenic mice, these probes are revealing new
and unanticipated local Ca2+ signalling events and the first chance to monitor endogenous Orai1 activity in native
T cells. In conjunction with T cell-specific Orai1 knockout mice, we use these tools to investigate: 1) how Orai1 is
activated at the single-molecule level; 2) how Orai1 channel activity varies in puncta and in native T cells; and 3)
how local Ca2+ signals modulate T cell motility during immune surveillance in the lymph node.

## Key facts

- **NIH application ID:** 10375085
- **Project number:** 3R01NS014609-40S1
- **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:** $47,790
- **Award type:** 3
- **Project period:** 2021-04-01 → 2023-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10375085

## Citation

> US National Institutes of Health, RePORTER application 10375085, Molecular Mechanisms of lon Channels in T Lymphocytes (3R01NS014609-40S1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10375085. Licensed CC0.

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