# Regulation of the Intestinal Ca2+ Channels TRPV6

> **NIH NIH R01** · RBHS-NEW JERSEY MEDICAL SCHOOL · 2020 · $402,109

## Abstract

PROJECT SUMMARY
Transient Receptor Potential Vanilloid 6 (TRPV6) is a Ca2+ selective ion channel playing important roles in
intestinal Ca2+ absorption, male fertility and cancer development. Its expression level in the intestines is
regulated by the active form of vitamin D. TRPV6 is member of the highly diverse TRP ion channel family. The
only known common functional feature among TRP channels is their dependence on, and modulation by
phosphoinositides, mostly phosphatidylinositol 4,5-bisphosphate [PI(4,5)P2]. Most TRP channels require
factors other than PI(4,5)P2 to open, which are often in complex interaction with PI(4,5)P2 regulation. This
complexity hinders understanding of the molecular mechanism of how PI(4,5)P2 opens these channels. TRPV6
is constitutively active, thus devoid of these complexities, and therefore is an ideal model to gain molecular
insight in its regulation by PI(4,5)P2. In the current proposal, we will study PI(4,5)P2 regulation of TRPV6
channels using a combination of computational and experimental approaches. We have built a homology
model of TRPV6 based on the recent nearly full-length, side-chain resolution structure of the related TRPV1
channels. We have computationally docked PI(4,5)P2 to both TRPV6 and TRPV1. In aims 1 and 2 we will use
a combination of electrophysiological techniques and further computational simulations to test predictions of
our model, and to gain insight into how PI(4,5)P2 open these channels. TRPV6 channels are constitutively
active, but undergo Ca2+ induced inactivation, similar to many other Ca2+ channels, presumably to avoid toxic
Ca2+ overload. In the previous funding period we developed a mutant of TRPV6 that is resistant to inhibition by
PI(4,5)P2 depletion, due to its high affinity for this lipid. We also identified a mutant that does not bind
calmodulin (CaM), thus it is resistant to inhibition by this Ca2+ binding protein. In aim 3, we will use these two
mutants, as well as fluorescence-based monitoring of CaM association with the channel, and depletion of
PI(4,5)P2 in measurements performed simultaneously with patch clamp recording of channel activity. These
experiments will dissect the roles of CaM and PI(4,5)P2 depletion in Ca2+-induced inactivation of channel
activity.

## Key facts

- **NIH application ID:** 9851873
- **Project number:** 5R01GM093290-09
- **Recipient organization:** RBHS-NEW JERSEY MEDICAL SCHOOL
- **Principal Investigator:** Vincenzo Carnevale
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $402,109
- **Award type:** 5
- **Project period:** 2011-04-01 → 2022-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9851873

## Citation

> US National Institutes of Health, RePORTER application 9851873, Regulation of the Intestinal Ca2+ Channels TRPV6 (5R01GM093290-09). Retrieved via AI Analytics 2026-06-05 from https://api.ai-analytics.org/grant/nih/9851873. Licensed CC0.

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