# Store-operated channels in the nervous system

> **NIH NIH R01** · NORTHWESTERN UNIVERSITY · 2022 · $395,379

## Abstract

Astrocytes comprise the major glial cell type in the brain and regulate numerous brain functions
including neural development, clearance of neurotransmitters, and regulation of blood flow. Recent
evidence indicates that astrocytes also play important roles in regulating neuronal excitability and
synaptic transmission by secreting a variety of neuroactive factors including proinflammatory
cytokines. These cytokines evoke a vast array of changes in neuronal and glial function including
alterations in Ca2+ signaling and synaptic transmission, which implicated in pathologies such as
neuropathic pain. In particular, following nerve injury, inflammatory cytokines including TNFα,
IL1β , and IL-6 are rapidly produced by glial cells to enhance the strength of excitatory synaptic
transmission in nociceptive circuits in the spinal cord and induce chronic pain. While microglia, a
macrophage-like cell type in the brain have received the lion's share of the attention in this
process, the role of astrocytes and the cellular checkpoints that regulate this process are less well
understood. Our preliminary findings indicate that store-operated Ca2+ release-activated Ca2+
(CRAC) channels are a major mechanism for purinergic-evoked Ca2+ signals in astrocytes and
their activation in spinal astrocytes strongly stimulates the transcription and secretion of a wide
range of proinflammatory cytokines and chemokines. Based on this evidence, we hypothesize that
CRAC channels are essential regulators of astrocyte-mediated neuroinflammation in neuropathic
pain. We propose three specific aims to address this hypothesis: 1) Define the role of CRAC
channels for agonist-evoked Ca2+ elevations and the inflammatory output of astrocytes, 2)
Determine the contributions of CRAC channel-mediated inflammatory cytokines for the
maladaptive potentiation of synaptic transmission in the dorsal horn of the spinal cord following
nerve injury, and 3) examine the in vivo relevance of CRAC channel-mediated inflammatory
cytokine production from astrocytes for neuropathic pain. We will approach these questions using
genetic knockouts of CRAC channel proteins in astrocytes, biochemical and transcriptome analysis
of cytokine synthesis, slice electrophysiology, Ca2+ imaging, and behavioral analysis. Results from
these studies will advance our understanding of the physiological role of CRAC channels for
regulating astrocyte-mediated neuroinflammation and aid the quest for developing new astrocyte-targeted therapies for pathological diseases affecting brain function.

## Key facts

- **NIH application ID:** 10434916
- **Project number:** 5R01NS057499-15
- **Recipient organization:** NORTHWESTERN UNIVERSITY
- **Principal Investigator:** Murali Prakriya
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $395,379
- **Award type:** 5
- **Project period:** 2007-02-13 → 2024-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10434916

## Citation

> US National Institutes of Health, RePORTER application 10434916, Store-operated channels in the nervous system (5R01NS057499-15). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10434916. Licensed CC0.

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