# Structure-function studies of IP3R channels

> **NIH NIH R01** · UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON · 2020 · $474,723

## Abstract

Project Summary/Abstract
Inositol 1,4,5-trisphosphate receptors (IP3R) are intracellular Ca2+ channels localized to the endoplasmic
reticulum (ER) membranes in almost every cell type. The rapid flux of Ca2+ through IP3R channels from the ER
to the cytosol is central to numerous and markedly different cellular actions, ranging from contraction to
secretion, from proliferation to cell death. 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. 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. This proposal builds on extensive advances we made recently in structural studies of
neuronal type 1 IP3R (IP3R1), the predominant type of IP3-gated Ca2+ release channel in cerebellar Purkinje
cells. We aim to uncover high-resolution architecture of the entire tetrameric 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
IP3R 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:** 9995271
- **Project number:** 2R01GM072804-10A1
- **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:** 2020
- **Award amount:** $474,723
- **Award type:** 2
- **Project period:** 2005-03-11 → 2024-02-29

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9995271

## Citation

> US National Institutes of Health, RePORTER application 9995271, Structure-function studies of IP3R channels (2R01GM072804-10A1). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9995271. Licensed CC0.

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