# Understanding Store-Operated Calcium Signal Transduction

> **NIH NIH R35** · PENNSYLVANIA STATE UNIV HERSHEY MED CTR · 2020 · $573,168

## Abstract

Project Summary
The remarkable spatial and temporal precision of Ca2+ signals finely controls a vast array of cellular functions.
Ca2+ signals reflect the function of highly coordinated Ca2+ sensors and Ca2+ channels. The interaction between
Ca2+ sensor STIM proteins in the ER and Orai Ca2+ channels in the PM, is crucial in Ca2+ signal generation. The
two proteins physically couple in ER-PM junctions, mediating “store-operated” Ca2+ signals, essential in
controlling gene expression, secretion, motility and growth. Their role in Ca2+ signaling is critical, and defects in
STIM or Orai proteins cause a spectrum of disorders including severe combined immunodeficiency, muscular
hypotonia, autoimmunity, skin dysplasia, and exocrine defects. Dysregulation of STIM/Orai expression is closely
linked to cardiovascular and airway remodeling, neurodegenerative disorders, altered immunity, and cancer. We
have defined much on the molecular properties and cellular organization of STIM and Orai proteins. We now
turn toward the nanoscale ER-PM junctional environment in which they operate. Junctional Ca2+ is critical in
generating both “local” Ca2+ signals and in sustaining “global” Ca2+ oscillations that extend across the cytoplasm
and penetrate the nucleus. Using a compendium of molecular probes, imaging technology, gene-deleted cellular
systems, and animal knockout models, our work is directed toward three major areas: (1) Identifying critical
differences in the disease-related STIM and Orai isoforms, focusing on operation of the widely expressed
STIM2.1 splice variant of STIM2 that lacks the critical Orai-binding domain; using super-resolution STED
microcopy and TIRF/FRET imaging we explore a model by which STIM2.1 disrupts the cross-linking of Orai
channel subtypes within junctions, and determine how clustering organizes the junctional Ca2+ signaling
machinery. (2) Defining the micro-physiological environment of Ca2+ entry junctions, utilizing genetically encoded
and optogenetically applied Ca2+ probes tagged onto STIM and Orai proteins to monitor the highly restricted
junctional Ca2+ micro-environment; using such measurements to explore how STIM-mediated clustering of Orai
channels controls local junctional Ca2+ signals, modifies the proximity of InsP3Rs and SERCA pumps, and
modulates the generation of global Ca2+ oscillations. (3) Understanding how store-operated Ca2+ signals are
transcriptionally transduced, exploring how the “STIM2 phenotype” in smooth muscle- and B cell-targeted
STIM1-deleted animals is related to STIM1/STIM2.1 expression levels and junctional Ca2+ signals, how STIM-
modulated Orai clustering controls specific NFAT subtype activation, and determining transcriptome changes
related to STIM type-specific Ca2+ signal generation. Our studies address the critical gap in our knowledge of
how junctional Ca2+ tunes the generation of local and global Ca2+ signals. The central role of STIM/Orai-mediated
store-operated Ca2+ signals in cell physiology...

## Key facts

- **NIH application ID:** 9926294
- **Project number:** 5R35GM131916-02
- **Recipient organization:** PENNSYLVANIA STATE UNIV HERSHEY MED CTR
- **Principal Investigator:** Donald L Gill
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $573,168
- **Award type:** 5
- **Project period:** 2019-06-01 → 2024-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9926294

## Citation

> US National Institutes of Health, RePORTER application 9926294, Understanding Store-Operated Calcium Signal Transduction (5R35GM131916-02). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/9926294. Licensed CC0.

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