The clinical challenge of GPCRs in wound healing kinetics

In oral surgery and implantology, the predictability of outcomes relies on the control of the four phases of wound healing: haemostasis, inflammation, proliferation and remodelling. While the clinical aspect is well documented, the molecular regulation of these stages largely depends on G protein-coupled receptors (GPCRs). This study analyses how this superfamily of over 800 receptors orchestrates the tissue response, from the initial recruitment of neutrophils to the final differentiation of keratinocytes.

The objective of this work is to map the GPCR signalling pathways — notably Hedgehog-GLI, Hippo-YAP1 and Wnt/β-catenin — involved in regeneration. The study explores the hypothesis that modulating the activity of these receptors, via specific agonists or antagonists (such as those targeting P2Y12 or adenosine receptors), can radically alter immune cell infiltration and accelerate wound closure rates. For the practitioner, understanding these mechanisms is crucial to consider new therapeutic approaches aimed at optimising the biological response, particularly in contexts of compromised healing.

Mapping GPCR mechanisms in tissue repair

This scientific review examines the involvement of G protein-coupled receptors (GPCRs) across the four stages of tissue repair: haemostasis, inflammation, proliferation and remodelling. The corpus analyses the 800 members of this protein superfamily, segmented into 6 distinct classes, to identify their influence on post-injury cellular dynamics.

The analysis protocol focuses on signal transduction via the Gα subunits (Gαs, Gαi/o, Gαq/11, Gα12/13). The review specifically evaluates the following mechanisms:

• Haemostasis: critical role of signals transmitted by P2Y12 receptors and platelet-activating factor receptors (PAFR) in platelet activation.
• Inflammatory phase: recruitment of neutrophils and macrophages mediated by chemokine receptors, purinergic receptors and formyl peptide receptors (FPR).
• Biochemical mediators: impact of molecules such as IL-1, TNF-α, serotonin, histamine, LTB4 and IL-3, as well as the release of reactive oxygen species (ROS).
• Regeneration pathways: activation of the Hedgehog-GLI, Hippo-YAP1 and Wnt/β-catenin cascades regulating the proliferation of keratinocytes and fibroblasts.

Finally, the analysis examines the influence of adenosine receptors and purinergic receptors (P2Y2, P2Y12) on cell migration and re-epithelialisation, based on integrin α3 expression data and phosphorylation of the ERK1/2 and Akt/PKB pathways.

GPCR signalling: an architecture with 800 variants

G protein-coupled receptors (GPCRs) represent the largest family of surface receptors, with over 800 members classified into 6 distinct categories. Their activation triggers the dissociation of the Gα and Gβγ subunits, initiating specific cascades depending on the Gα protein involved. The study identifies four subclasses of Gα proteins dictating the cellular response:

Focus on the purinergic pathway and the P2Y2 receptor

The study highlights a complex regulatory role of the P2Y2 receptor in the proliferation phase. Unlike other pro-healing receptors, the binding of ATP or UTP to the P2Y2 receptor leads to a modulation of cellular plasticity:

• Inhibition of keratinocyte proliferation.
• Retraction of lamellipodia and disorganisation of the actin network.
• Loss of α3 integrin expression at the cell periphery, causing the dissolution of local contacts.

At the molecular level, P2Y2 activation blocks the growth factor-induced phosphorylation of ERK1/2 and Akt/PKB. This mechanism is strictly dependent on the Gα(q/11) subunit. The study highlights that the combined suppression of Gα11 and Gαq causes a major migratory defect in keratinocytes, significantly delaying re-epithelialisation in vivo.

Multicellular regulation by GPCRs

Beyond keratinocytes, GPCRs coordinate the entire tissue response across different phases:

• Haemostasis: P2Y12 receptors and platelet-activating factor receptors (PAFR) are essential for platelet activation.
• Inflammation: Chemokine receptors, formyl peptide receptors (FPR) and purinergic receptors orchestrate the migration of immune cells to the site of injury.
• Proliferation: Adenosine receptors, protease-activated receptors (PAR) and the Smoothened (Smo) receptor regulate the proliferation and migration of endothelial cells, macrophages and keratinocytes.

GPCR: The new orchestrators of tissue repair

The aim of this review is to go beyond the traditional view of wound healing to focus on G protein-coupled receptors (GPCRs). With over 800 members, this family of receptors acts as a central control system regulating immune cell migration and keratinocyte proliferation. Clinically, the study emphasises that the manipulation of these receptors via agonists or antagonists could radically transform the management of complex wounds.

A major point concerns the specificity of purinergic pathways. The P2Y12 receptor, activated by ADP, is distinguished by its ability to accelerate new tissue formation. Conversely, the activation of the P2Y2 receptor by ATP or UTP appears to exert an inhibitory effect on keratinocyte proliferation, a mechanism dependent on the Gα(q/11) subunit. This duality demonstrates that wound healing does not depend solely on the presence of growth factors, but on the fine balance between different GPCR signalling pathways.

Current limitations lie in the complexity of these signalling cascades (Gαs, Gαi, Gαq). Although the A2AR-YAP axis opens up promising avenues for tissue remodelling, the transition to targeted chairside therapies still requires clarifying the interaction between these receptors and the inflammatory microenvironment, particularly in patients presenting with systemic healing defects.

In practical terms, for the practitioner:

• Complex wound healing: P2Y12 receptor agonism (via ADP) is a major therapeutic avenue to accelerate tissue formation and resolve inflammation, particularly in diabetic patients.
• Angiogenesis driver: Adenosine receptors (A1, A2A, A2B) directly regulate endothelial proliferation and progenitor homing, critical factors for the success of grafts and implantology.
• Epithelialisation management: Gα(q/11) signalling is essential for keratinocyte migration; any defect in this cascade, particularly via the P2Y2 pathway, compromises the hermetic closure of the surgical site.

Technical glossary of wound healing mechanisms

GPCR (G protein-coupled receptors): Superfamily of seven-transmembrane domain receptors regulating cellular signal transduction. They orchestrate immune cell recruitment and epidermal proliferation cascades (Hedgehog-GLI, Wnt/β-catenin).

Gα subunits (Gαq/11, Gαs, Gαi): Intracellular signalling proteins coupled to GPCRs. The Gαq/11 class triggers calcium signalling, while the Gαs and Gαi classes modulate cyclic AMP (cAMP) levels.

Smo (Smoothened): Specific GPCR-type receptor involved in the Hedgehog pathway. It directly regulates the proliferation, differentiation and migration of keratinocytes and endothelial cells.

FPRs (Formyl Peptide Receptors): GPCRs mediating leukocyte chemotaxis. They direct the migration of immune cells to the lesion site to regulate the local inflammatory response.

Neutrophils: First immune cells recruited by inflammatory mediators (IL-1, TNF-α). They perform biological debridement through phagocytosis and the release of reactive oxygen species (ROS) and elastases.

Remodelling: Final phase of the tissue repair process where fibroblasts secrete hyaluronic acid and proteoglycans to organise the formation of mature collagen fibres.

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