# Structure and function of inositol triphosphate receptors

> **NIH NIH R01** · VANDERBILT UNIVERSITY · 2024 · $47,083

## Abstract

PROJECT SUMMARY
 Inositol 1,4,5-triphosphate receptors (IP3Rs) integrate diverse signals generated by hormones, growth
factors, neurotransmitters, and changes in metabolic state to modulate downstream signaling in all cell types.
IP3Rs are ligand-gated ion channels that are further regulated by allosteric and covalent mechanisms,
mediating Ca2+ release from the endoplasmic reticulum (ER). The resulting increases of cytoplasmic and
mitochondrial Ca2+ concentrations regulate many physiological processes (e.g., learning, memory, membrane
trafficking, synaptic transmission, secretion, motility, membrane excitability, gene expression, cell division, and
apoptosis). Furthermore, pathological dysregulation of IP3Rs and calcium signaling is implicated in cancer,
neurodegenerative, autoimmune, and metabolic diseases, making IP3Rs promising targets for treatment of
these diseases. Despite recent advances in structural studies, fundamental questions regarding the
mechanisms of ligand interactions and channel gating remain mostly unanswered, in part because of the large
size and complexity of IP3Rs and the limited availability of specific pharmacological tools.
 In this proposal, we will (Aim 1) combine cryo-electron microscopy (cryo-EM) and X-ray crystallography
in conjunction with functional IP3R assays based on fluorescence-based calcium imaging to elucidate the
general themes of IP3R gating cycle and molecular basis for receptor inhibition by small molecules.
 Our recently published data revealed that the IP3 binding site is occupied by a loop that we have termed
the self-binding peptide (SBP), which is located distantly in the primary sequence. We hypothesize that the
SBP is a novel regulatory site in IP3Rs that can modulate the apparent affinity for IP3, and thereby Ca2+
channel activity, and that the divergence of SBP sequences between IP3R subtypes contributes to their distinct
regulatory properties. We will perform (Aim 2) functional and structural studies on IP3R subtypes and SBP
mutants to test this hypothesis and identify the structural determinants of this interaction.
 Completion of these aims will yield unparalleled mechanistic insight into IP3R gating and regulation,
potentially leading to the development of novel and specific pharmacological modulators of IP3Rs. In addition
to being used as a long-sought research tools to study IP3Rs, these compounds will serve as a starting point
for development of novel therapeutic approaches to treat diseases associated with aberrant IP3R activity.

## Key facts

- **NIH application ID:** 11100747
- **Project number:** 3R01GM141251-04S1
- **Recipient organization:** VANDERBILT UNIVERSITY
- **Principal Investigator:** ERKAN KARAKAS
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $47,083
- **Award type:** 3
- **Project period:** 2021-09-10 → 2025-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/11100747

## Citation

> US National Institutes of Health, RePORTER application 11100747, Structure and function of inositol triphosphate receptors (3R01GM141251-04S1). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/11100747. Licensed CC0.

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