# Discovery of synthetic and endogenous ligands for orphan GPCR GPR156

> **NIH NIH R01** · UNIVERSITY OF ROCHESTER · 2024 · $659,164

## Abstract

G Protein coupled Receptors (GPCRs) regulate every aspect of human physiology. However, the endogenous
ligands activating ~100 GPCRs are still unknown, hence they are named orphan GPCRs. Considering their
understudied biology and established physiological roles, orphan GPCRs represent unexploited
pharmacological targets. The quest for endogenous and synthetic compounds modulating their activity is
significant for both understanding their biology and developing novel therapeutics. Using an innovative cell-
based assay, we recently established Gi/o/z coupling for several orphan GPCRs. Building on this discovery, we
optimized a platform to screen candidate ligands based on the heterologous co-expression of orphan GPCRs
and a multicomponent activity biosensor. The ultimate goal of this project is to identify pharmacological
modulators, endogenous ligands, and binding partners for GPR156, a clinically relevant target for the treatment
of hearing and balance disorders with unexplored roles in the central nervous system. Our preliminary data
support the feasibility of the approach and also establish the presence of endogenous ligands in the brain.
Thus, the identification of these endogenous ligands will constitute an additional goal of our proposal that we
will pursue applying innovative proximity-mediated labeling technologies. Activity of identified ligands and
function of interacting proteins identified by proteomics analysis will be validated in a physiologically relevant
system. In fact, GPR156 controls hair cell orientation in auditory and balance organs, with GPR156 gene
mutations leading to deafness and balance disorders in patients. Finally, combining proteomics analysis and
mouse genetics, we will define components of GPR156 signaling complex and determine their role in
establishing planar cell polarity in the mouse inner ear.

## Key facts

- **NIH application ID:** 10987832
- **Project number:** 1R01DC022104-01A1
- **Recipient organization:** UNIVERSITY OF ROCHESTER
- **Principal Investigator:** Cesare Orlandi
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $659,164
- **Award type:** 1
- **Project period:** 2024-08-15 → 2029-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10987832

## Citation

> US National Institutes of Health, RePORTER application 10987832, Discovery of synthetic and endogenous ligands for orphan GPCR GPR156 (1R01DC022104-01A1). Retrieved via AI Analytics 2026-06-12 from https://api.ai-analytics.org/grant/nih/10987832. Licensed CC0.

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