# Ca2+ waves in hepatocytes: Mechanisms and effects

> **NIH NIH R01** · YALE UNIVERSITY · 2022 · $514,564

## Abstract

PROJECT SUMMARY
Bile secretion is one of the principal functions of the liver. Cholestasis, or impaired bile flow, is a cardinal
manifestation of liver disease. Cholestatic liver diseases are an important group of disorders, which collectively
represent the most common indication for pediatric liver transplant and account for one in ten of all liver
transplants. This project investigates a basic biological mechanism in epithelial biology that is directly relevant
for the regulation of secretion in hepatocytes in health and disease. Calcium signals in hepatocytes are formed
largely by calcium release from the inositol 1,4,5-trisphosphate (InsP3) receptor (InsP3R), which is an InsP3-
gated calcium channel in the endoplasmic reticulum (ER). The type II InsP3R (InsP3R-2) is the predominant
isoform in hepatocytes, constituting 80% of the total pool of InsP3Rs, and is most concentrated in a specialized
region of the ER beneath the canalicular membrane. Calcium signals in hepatocytes generally begin as calcium
waves that originate in this region, and the apical pool of InsP3R-2 in hepatocytes is important for mediating
calcium waves and canalicular secretion. In contrast, the type I InsP3R (InsP3R-1), which constitutes the
remaining 20% of the InsP3R pool in hepatocytes, preferentially localizes to a different subcellular region and
does not affect secretion. The hypothesis of this project is that the factors that regulate the expression and
subcellular distribution of InsP3R-2 also regulate hepatocyte secretion, so that cholestasis is mediated by these
effects on InsP3R-2. In particular, we will test whether cholestatic liver diseases are due in part to impaired
expression and/or peri-canalicular targeting of InsP3R-2, which in turn impairs polarized calcium waves in the
cytosol and downstream events including regulation of the bile acid transporter Bsep and the organic anion
transporter Mrp2. This hypothesis will be tested through the following specific aims: (1) We will determine the
genetic and epigenetic factors that regulate expression of InsP3R-2 in hepatocytes. (2) We will determine the
molecular basis for, and cellular effects of, targeting InsP3R-2 to the ER-canalicular membrane interface. (3) We
will determine whether and how InsP3R-2 expression and/or pericanalicular targeting is impaired in hepatocytes
during canalicular cholestasis. We also will determine whether the efficacy of new therapies being developed
for treatment of cholestatis disorders is mediated in part by modulating InsP3R-2. Collectively, these studies will
break new ground in our understanding of the ways in which signaling microdomains are established in
hepatocytes, and have the potential to establish new paradigms for translating these observations into
understanding the mechanistic basis for a range of clinically significant human liver diseases.

## Key facts

- **NIH application ID:** 10388244
- **Project number:** 5R01DK114041-05
- **Recipient organization:** YALE UNIVERSITY
- **Principal Investigator:** MICHAEL H NATHANSON
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $514,564
- **Award type:** 5
- **Project period:** 2018-04-01 → 2024-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10388244

## Citation

> US National Institutes of Health, RePORTER application 10388244, Ca2+ waves in hepatocytes: Mechanisms and effects (5R01DK114041-05). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10388244. Licensed CC0.

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