# Structure-Function Studies Of IP3R Channels

> **NIH NIH R01** · UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON · 2021 · $117,428

## Abstract

Project Summary/Abstract (parent award)
Ca2+ release from internal stores is mediated by inositol 1,4,5-trisphosphate receptors (IP3R) that belong to a
family of intracellular Ca2+ channels localized to the endoplasmic reticulum membranes in almost every cell
type. The rapid flux of Ca2+ through IP3R channels is central to numerous and markedly different cellular
actions, ranging from contraction to secretion, from proliferation to cell death. Dysfunction of IP3Rs is
implicated in numerous neurodegenerative diseases, such as Alzheimer’s and Huntington’s disease, cardiac
arrhythmias, autoimmune disease, ataxia, stroke and cancer. Despite established significance of IP3Rs in
physiology and pathology, the molecular mechanisms underlying function of these channels, both in native and
disease states, remain poorly understood. This is mainly due to the lack of atomic-level details of IP3R
structure. The long-term goals of our research are to understand the mechanisms of ion permeation and gating
in the family of IP3R channels, and how intracellular binding partners regulate the channel function. The focus
of this proposal is neuronal type 1 IP3R (IP3R1), the predominant type of IP3-gated Ca2+ release channel in
cerebellar Purkinje cells. This proposal builds on extensive advances we made recently in structural studies of
this ion channel. We aim to uncover high-resolution architecture of IP3R1 and to delineate conformational
changes in the channel that underlie its gating motion and regulation by an array of intracellular molecules
ranging from ions and small chemical compounds to proteins. Our research efforts will include cryo-EM
structure determination, biochemistry, biophysical, mutagenesis and electrophysiological studies to address
channel structure-function Built upon the complementary expertise of established investigators with compelling
preliminary data support, the proposed studies will unveil the structural and mechanistic basis for IP3R1
function and will elucidate how defects in mechanisms regulating the channel’s gating can lead to abnormal
cell Ca2+ levels underlying numerous diseases. Our research is innovative since little is known at the atomic
level about the IP3R function. With these studies accomplished, we will establish a detailed structural
framework for understanding how the IP3R selectively senses and decodes multiple ligand-binding signals into
gating motions that enable the passage of Ca2+ through the channel. This knowledge is crucial for developing
new ways to control channel function. Overall, the proposed studies are highly significant, as they will provide
valuable mechanistic insights into Ca2+ transfer across biological membranes illuminating the pathological
consequences of deregulated Ca2+ signaling, that will ultimately aid in search for novel therapies targeting the
IP3R channel family.

## Key facts

- **NIH application ID:** 10378168
- **Project number:** 3R01GM072804-11S1
- **Recipient organization:** UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON
- **Principal Investigator:** Irina I Serysheva
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $117,428
- **Award type:** 3
- **Project period:** 2005-03-11 → 2024-02-29

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10378168

## Citation

> US National Institutes of Health, RePORTER application 10378168, Structure-Function Studies Of IP3R Channels (3R01GM072804-11S1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10378168. Licensed CC0.

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