GPCR Screening Reveals that the Metabolite Receptor HCAR3 Regulates Epithelial Proliferation, Migration, and Cellular Respiration.

Epithelial cells in the skin and other tissues rely on signals from their environment to maintain homeostasis and respond to injury, and GPCRs play a critical role in this communication. A better understanding of the GPCRs expressed in epithelial cells will contribute to understanding the relationship between cells and their niche and could lead to developing new therapies to modulate cell fate. This study used human primary keratinocytes as a model to investigate the specific GPCRs regulating epithelial cell proliferation and differentiation. We identified 3 key receptors-HCAR3, LTB4R, and GPR137-and found that knockdown of these receptors led to changes in numerous gene networks that are important for maintaining cell identity and promoting proliferation while inhibiting differentiation. Our study also revealed that the metabolite receptor HCAR3 regulates keratinocyte migration and cellular metabolism. Knockdown of HCAR3 led to reduced keratinocyte migration and respiration, which could be attributed to altered metabolite use and aberrant mitochondrial morphology caused by the absence of the receptor. This study contributes to understanding the complex interplay between GPCR signaling and epithelial cell fate decisions.

A GPCR screening in human keratinocytes identifies that the metabolite receptor HCAR3 controls epithelial proliferation, migration, and cellular respiration.

Epithelial cells in the skin and other tissues rely on signals from their environment to maintain homeostasis and respond to injury, and G protein-coupled receptors (GPCRs) play a critical role in this communication. A better understanding of the GPCRs expressed in epithelial cells will contribute to understanding the relationship between cells and their niche and could lead to developing new therapies to modulate cell fate. This study used human primary keratinocytes as a model to investigate the specific GPCRs regulating epithelial cell proliferation and differentiation. We identified three key receptors, hydroxycarboxylic acid-receptor 3 (HCAR3), leukotriene B4-receptor 1 (LTB4R), and G Protein-Coupled Receptor 137 (GPR137) and found that knockdown of these receptors led to changes in numerous gene networks that are important for maintaining cell identity and promoting proliferation while inhibiting differentiation. Our study also revealed that the metabolite receptor HCAR3 regulates keratinocyte migration and cellular metabolism. Knockdown of HCAR3 led to reduced keratinocyte migration and respiration, which could be attributed to altered metabolite use and aberrant mitochondrial morphology caused by the absence of the receptor. This study contributes to understanding the complex interplay between GPCR signaling and epithelial cell fate decisions.

The landscape of GPCR signaling in the regulation of epidermal stem cell fate and skin homeostasis.

Continuous integration of signals from the micro and macro-environment is necessary for somatic stem cells to adapt to changing conditions, maintain tissue homeostasis and activate repair mechanisms. G-protein coupled receptors (GPCRs) facilitate this integration by binding to numerous hormones, metabolites and inflammatory mediators, influencing a diverse network of pathways that regulate stem cell fate. This adaptive mechanism is particularly relevant for tissues that are exposed to environmental assault, like skin. The skin is maintained by a set of basal keratinocyte stem and progenitor cells located in the hair follicle and interfollicular epidermis, and several GPCRs and their signaling partners serve as makers and regulators of epidermal stem cell activity. GPCRs utilize heterotrimeric G protein dependent and independent pathways to translate extracellular signals into intracellular molecular cascades that dictate the activation of keratinocyte proliferative and differentiation networks, including Hedgehog GLI, Hippo YAP1 and WNT/ß-catenin, ultimately regulating stem cell identity. Dysregulation of GPCR signaling underlines numerous skin inflammatory diseases and cancer, with smoothened-driven basal cell carcinoma being a main example of a GPCR associated cancer. In this review, we discuss the impact of GPCRs and their signaling partners in skin keratinocyte biology, particularly in the regulation of the epidermal stem cell compartment.

Activation of G-Protein Coupled Receptor-Gαi Signaling Increases Keratinocyte Proliferation and Reduces Differentiation, Leading to Epidermal Hyperplasia.

G-protein coupled receptors (GPCRs) and their associated heterotrimeric G proteins impinge on pathways that control epithelial cell self-renewal and differentiation. Although it is known that Gαs protein signaling regulates skin homeostasis in vivo, the role of GPCR-coupled Gαi proteins in the skin is unclear. Here, by using a chemogenetic approach, we demonstrate that GPCR-Gαi activation can regulate keratinocyte proliferation and differentiation and that overactivation of Gαi-signaling in the basal compartment of the mouse skin can lead to epidermal hyperplasia. Our results expand our understanding of the role of GPCR-cAMP signaling in skin homeostasis and reveal overlapping and divergent roles of the cAMP-regulating heterotrimeric Gαs and Gαi proteins in keratinocytes.