# Electrophysiology of nuclear membrane InsP3 receptor

> **NIH NIH R37** · UNIVERSITY OF PENNSYLVANIA · 2020 · $502,320

## Abstract

We previously identified a novel mechanism that directly links the inositol trisphosphate receptor (InsPSR)
Ca2+ release ion channel to programmed cell death. We extended our new insights into the biochemical
and functional interactions of the InsPSR and anti-apoptotic Bcl-2 family proteins with the discovery of an
essential requirement of InsPSR activity to suppress macroautophagy and maintain efficient mitochondrial
respiration and normal cell bioenergetics. The InsPSR participates in generation of complex Ca2+ signals
that regulate many physiological processes in cells, including, as we have discovered, autophagy and basal
metabolism, as well as cell survival and death decisions. The studies undertaken to explore this regulation
have led to the development of an important new paradigm regarding the regulation of cellular bioenergetics
that involves a ubiquitous pathway involving constitutive Ca2+ delivery from the ER to mitochondria
mediated by Ca2+ release through the InsPSR and Ca2+ uptake by the mitochondrial Ca2+ uniporter
complex. Although our studies have previously defined many of the features of the InsPSR ion channel, the
details of the mechanisms of permeation, gating and regulation of the complex of the mitochondrial Ca2+
uniporter are largely unknown. Our preliminary studies suggest that whereas normal and cancer cells have
a similar reliance on constitutive mitochondrial Ca2+ uptake for maintenance of optimal bioenergetics,
cancers cells are addicted to it since they cannot survive when it is blocked. The mechanisms that underlie
this differential sensitivity between normal and cancer cells remain to be elucidated, with obvious clinical
relevance. We will employ biophysical (electrophysiology, optical imaging), biochemical, genetic and cell
biological approaches to define the mechanistic and structural basis for the uniporter Ca2+ channel
complex. Furthermore, we will define the roles of this complex and the InsPSR as molecular targets for
cancer cell growth, by use of metabolomics, cell biological and genetic approaches and in vitro and in vivo
mouse models.
RELEVANCE (See instructions):
The ubiquitous expression of constitutive ER-mito Ca2+ transfer has relevance for many physiological and
pathophysiological processes, including cancer. A complete molecular understanding of the Ca2+ uniporter
complex and appreciation of how cancer cells are addicted to its activity will provide insights that may lead
to therapeutic approaches.

## Key facts

- **NIH application ID:** 9899999
- **Project number:** 5R37GM056328-22
- **Recipient organization:** UNIVERSITY OF PENNSYLVANIA
- **Principal Investigator:** James Kevin FOSKETT
- **Activity code:** R37 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $502,320
- **Award type:** 5
- **Project period:** 1999-02-01 → 2022-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9899999

## Citation

> US National Institutes of Health, RePORTER application 9899999, Electrophysiology of nuclear membrane InsP3 receptor (5R37GM056328-22). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/9899999. Licensed CC0.

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