# Mechanisms of Adhesion GPCR Action

> **NIH NIH R01** · UNIVERSITY OF MICHIGAN AT ANN ARBOR · 2022 · $366,600

## Abstract

Summary/Abstract: GPR56/ADGRG1 is a deorphanized brain Adhesion G protein Coupled Receptor (AGPCR)
with a physiological ligand, collagen. We present new evidence that GPR56 is present on the surface of human
and mouse platelets. This is very intriguing considering that autonomous platelet activation that leads to clot
formation is mediated by platelet interactions with collagen that becomes exposed at sites of vessel injury. We
found that pharmacological activation of platelet GPR56 is sufficient to elicit the physiological platelet activation
program required for wound healing (hemostasis) and blood clotting (thrombosis). Moreover, Gpr56 knockout
mice have a severe bleeding disorder and dramatic defects in clot formation in mouse vessel wall injury models.
We hypothesize that GPR56 is the platelet collagen receptor that mediates the initial G protein 12/13-dependent
platelet shape changes while platelets roll/translocate along exposed collagen to their site of stable adhesion at
the lagging edges of blood vessel wounds. We will investigate platelet GPR56-mediated G protein signaling,
platelet shape changes, in vitro platelet activation, and the role of GPR56 in mouse models of hemostasis and
thrombosis. We found compelling preliminary evidence that platelets from Gpr56 knockout mice are dramatically
defective in adhering to an immobilized collagen surface when mouse blood is flowed over the surface at high
shear force. We propose that GPR56 is not directly involved in stable platelet adhesion, but as platelets tumble
across the collagen surface, GPR56 is stimulated to cause the shape changes that allow platelets to then stably
adhere via distinct non-GPCR collagen receptors. Before discovering GPR56 on platelets we proposed a
general model of AGPCR activation that required anchoring of the receptor N-termini, and shear force-mediated
receptor dissociation that leads to exposure of the AGPCR tethered agonists to induce G protein signaling. The
conditions experienced by platelet-borne GPR56 align remarkably well with this theoretical model. Our work
also includes conducting biochemical studies using newly developed photo-crosslinking agonist probes to define
the agonist binding sites of the related AGPCRs, GPR56 and GPR114.

## Key facts

- **NIH application ID:** 10374884
- **Project number:** 5R01GM120110-06
- **Recipient organization:** UNIVERSITY OF MICHIGAN AT ANN ARBOR
- **Principal Investigator:** Gregory Gordon Tall
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $366,600
- **Award type:** 5
- **Project period:** 2016-09-15 → 2024-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10374884

## Citation

> US National Institutes of Health, RePORTER application 10374884, Mechanisms of Adhesion GPCR Action (5R01GM120110-06). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10374884. Licensed CC0.

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