# Molecular mechanisms of TRPV5 gating

> **NIH NIH R01** · UNIVERSITY OF PENNSYLVANIA · 2021 · $393,010

## Abstract

PROJECT SUMMARY/ABSTRACT
 Nephrolithiasis, generally known as kidney stones, is a common disease that affects approximately 30
million Americans. One of the most critical risk factors for kidney stone formation is hypercalciuria, or high
levels of urine calcium (Ca2+). The transient receptor potential vanilloid type 5 (TRPV5) channel, which is
primarily expressed in the kidney, has been found to be essential for reabsorption of Ca2+ into the blood. Loss
or dysfunction of TRPV5 has been shown to severely increase urine Ca2+ levels and the occurrence of kidney
stones. TRPV5 is found in the apical membrane of the nephron epithelium and allows Ca2+ reabsorption from
the urine along its concentration gradient. In the absence of modulators, TRPV5 has been proposed to be
constitutively active. Endogenous modulators such as calmodulin (CaM) and phosphatidylinositol 4,5-
bisphosphate (PI(4,5)P2) have been found to stabilize TRPV5 in the closed or open conformation, respectively.
Protein kinase C (PKC)-mediated TRPV5 phosphorylation at Ser299 and Ser654 residues has been shown to
enhance open probability of the channel. Small molecule antifungals like econazole and miconazole have been
demonstrated to inhibit TRPV5. However, molecular details of this channel modulation and gating are poorly
understood. Therefore, the goal of this proposal is to utilize cryo-electron microscopy (cryo-EM) in conjunction
with biochemical, electrophysiological and computational approaches to uncover the molecular mechanisms of
TRPV5 gating. An in-depth investigation of TRPV5 at the atomic level will pave the way for targeted drug
discovery for the control and treatment of hypercalciuria and nephrolithiasis.

## Key facts

- **NIH application ID:** 10167732
- **Project number:** 5R01GM129357-04
- **Recipient organization:** UNIVERSITY OF PENNSYLVANIA
- **Principal Investigator:** Vera Moiseenkova-Bell
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $393,010
- **Award type:** 5
- **Project period:** 2018-09-10 → 2022-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10167732

## Citation

> US National Institutes of Health, RePORTER application 10167732, Molecular mechanisms of TRPV5 gating (5R01GM129357-04). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10167732. Licensed CC0.

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