# Develop enabling biochemical and structural tools for dissecting the roles of PKD2L2 in metabolism

> **NIH NIH R03** · UTAH STATE HIGHER EDUCATION SYSTEM--UNIVERSITY OF UTAH · 2022 · $153,500

## Abstract

Project Summary
 The polycystin family falls into two classes of integral membrane proteins: 1) the PKD1-type clade
comprises five 11-transmembrane (TM) spanning receptor-like proteins (PKD1, PKD1L1, PKD1L2, PKD1L3, and
PKD1REJ) characterized by a large N-terminal ectodomain that likely recognizes as-yet unknown ligand(s); and
2) the PKD2-type clade consists of three 6-TM spanning transient receptor potential (TRP) ion channels (PKD2,
PKD2L1, and PKD2L2). PKD1 and PKD2 are the two most extensively studied polycystin proteins largely
because inactivating mutations in either PKD1 or PKD2 cause a common, life-threatening, multisystem, and
incurable autosomal dominant polycystic kidney disease (ADPKD). We and others showed that PKD2 itself
functions as a non-selective, domain swapped cation channel. PKD2 additionally associates with PKD1 to form
a heteromeric receptor/ion channel complex at sensory cilia of renal epithelia where they may respond to as-yet
unknown chemical ligand(s) and/or mechanical force, contributing to the establishment and maintenance of the
exquisite tubular architecture of nephrons in the kidneys. The physiological functions and disease relevance of
other polycystin family members are poorly understood, although they also assemble into various complexes
that possibly serve as cellular sensors for detecting and responding to a diverse range of physiological and
environmental stimuli. PKD2L2 may participate in male reproduction as it is expressed in the testis and
contributes to Ca2+ signaling in sperms. The PKD2L2-/- mice generated by the Illuminating the Druggable
Genome (IDG) consortium exhibit altered glucose tolerance, which is an exciting discovery that suggests that
PKD2L2 may function as a Ca2+ channel that regulates Ca2+ signaling and insulin secretion in the pancreas. Built
on our successful biochemical, structural, and functional studies on PKD1 and PKD2 and a recent breakthrough
in determining a 3.0 Å PKD2L2 cryo-EM structure, here we will continue to develop enabling biochemical
reagents and structural models to lower the barriers to entry for other researchers who share the same
enthusiasm for the understudies PKD2L2 channel. Specifically, we will leverage our expertise in membrane
protein biochemistry and structural biology to: 1) determine additional cryo-EM structures for PKD2L2 that
capture the channel in new functional states along its gating cycle; and 2) develop specific and sensitive
antibodies and nanobodies for PKD2L2 that can be used to localize the channel in native tissues and cells, which
will provide insights into PKD2L2 functions by illuminating the cell types and tissues where the channel operates.

## Key facts

- **NIH application ID:** 10452211
- **Project number:** 1R03TR003650-01A1
- **Recipient organization:** UTAH STATE HIGHER EDUCATION SYSTEM--UNIVERSITY OF UTAH
- **Principal Investigator:** Erhu Cao
- **Activity code:** R03 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $153,500
- **Award type:** 1
- **Project period:** 2022-06-01 → 2023-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10452211

## Citation

> US National Institutes of Health, RePORTER application 10452211, Develop enabling biochemical and structural tools for dissecting the roles of PKD2L2 in metabolism (1R03TR003650-01A1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10452211. Licensed CC0.

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