# Regulation of the epithelial Ca2+ channels TRPV6 and TRPV5

> **NIH NIH R01** · RUTGERS BIOMEDICAL AND HEALTH SCIENCES · 2022 · $459,853

## Abstract

ABSTRACT
Transient Receptor Vanilloid 6 (TRPV6) and its close relative TRPV5 are Ca2+ selective epithelial ion
channels. The membrane phospholipid phosphatidylinositol 4,5-bisphosphate [PI(4,5)P2] is the
endogenous ligand of these channels that is required for their activity. These channels also undergo
Ca2+-induced inactivation which is mediated by binding of Ca2+-calmodulin (CaM) to the channel.
TRPV6 and TRPV5 are constitutively active, and their level of activity is determined by the balance
between the activating PI(4,5)P2 and the inhibitory CaM. In the previous funding period, we identified
the PI(4,5)P2 binding site in TRPV6 using homology modeling and site directed mutagenesis, which
was essentially identical to the experimentally determined PI(4,5)P2 binding site in the closely related
TRPV5. CryoEM structures for CaM and TRPV6 or TRPV5 also became available, showing a highly
consistent picture of one CaM molecule binding to the channel tetramer, and blocking the pore in a
fashion consistent with our experimental results. An important development during the previous
funding period was the finding that loss of function mutations in TRPV6 are associated with chronic
pancreatitis. The likely mechanism is reduced Ca2+ removal from pancreatic fluid in the acini or the
ducts leading to increased Ca2+ and premature activation of pancreatic digestive enzymes. Given the
crucial role of Ca2+ in digestive enzyme activation, small molecules that increase the activity of
TRPV6 can, in principle, be used as novel therapeutic approach to treat pancreatitis. The overall goal
of this application is to gain molecular insight into how the two key endogenous regulators PI(4,5)P2
and CaM gate TRPV6 and to use our molecular level understanding of their regulation to identify
small molecules that increase their activity. We will use a combination of computational and
experimental approaches to decipher the molecular mechanism of PI(4,5)P2 activation of TRPV6 and
TRPV5 in Aim1, to determine the relationship between CaM and PI(4,5)P2 regulation of TRPV6 in
Aim 2, and to identify small molecules that increase TRPV6 and/or TRPV5 activity by interfering with
CaM inhibition in Aim 3. This work will further our understanding of TRPV6 and TRPV5 gating, and
small molecules that enhance the activity of TRPV6 or TRPV5 can be used in future experiments to
explore the possibility of using this approach to treat or prevent pancreatitis and kidney stones.

## Key facts

- **NIH application ID:** 10538702
- **Project number:** 2R01GM093290-10
- **Recipient organization:** RUTGERS BIOMEDICAL AND HEALTH SCIENCES
- **Principal Investigator:** Vincenzo Carnevale
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $459,853
- **Award type:** 2
- **Project period:** 2011-04-01 → 2026-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10538702

## Citation

> US National Institutes of Health, RePORTER application 10538702, Regulation of the epithelial Ca2+ channels TRPV6 and TRPV5 (2R01GM093290-10). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10538702. Licensed CC0.

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