GPR4 Membrane Protein Introduction

Introduction of GPR4

GPR4 is a protein that in humans is encoded by the GPR4 gene. It is a member of the G-protein-coupled receptors (GPCRs) family activated by protons in the physiological pH range. During the past years, studies have suggested that GPR4 could act as acid sensors in diverse tissues, such as bone, kidney, and brain as well as in several cell types, including endothelial cells.

Function of GPR4 Membrane Protein

The pH-sensing G protein-coupled receptors (GPCRs) have been identified as a new class of receptors that are involved in sensing both local and systemic pH changes. Particular, members of these receptors have been implicated in various disease states associated with dysregulated pH homeostasis such as cancer, ischemia, metabolic acidosis, and inflammation. As a member of the pH-sensing GPCRs, GPR4 has been reported to be highly expressed in vascular endothelial cells (ECs) and blood vessel-rich tissues, such as the lung, kidney, heart, and liver. And it plays a key role as an acid sensor during blood vessel development, regulates outgrowth of small capillaries, and mediates an inflammatory response in endothelium exposed to acidic environments. Recently, GPR4 has been shown to mediate EC inflammatory responses to acidosis and is central for leukocyte-endothelium interaction. What’s more, studies have shown that GPR4 deficiency impairs acid excretion by the kidney, eliciting a mild non-gap metabolic acidosis similar to distal renal tubular acidosis in humans.

Fig.1 GPR4 signaling pathways and action modes of the imidazopyridine compound and psychosine as the GPR4 modulator and antagonist. (Tobo, 2015)

Application of GPR4 Membrane Protein in Literature

1. Wang Y., et.al. The proton-activated receptor GPR4 modulates intestinal inflammation. Journal of Crohn's and Colitis. 2017, 12(3):355-68. PubMed ID: 29136128
   
   

   This article investigates the role of GPR4 in intestinal inflammation. It indicates that GPR4 plays an important regulatory role in mucosal inflammation and provides a new link between tissue pH and the immune system. Furthermore, it also suggests that therapeutic inhibition of GPR4 may be beneficial for the treatment of IBD.

2. Dong B., et.al. GPR4 knockout improves renal ischemia-reperfusion injury and inhibits apoptosis via suppressing the expression of CHOP. Biochemical Journal. 2017, 474(24):4065-74. PubMed ID: 29089376
   
   

   This article investigates the effects and molecular mechanisms of GPR4 in cell apoptosis and renal ischemia-reperfusion (IR) injury. It suggests that GPR4 knockdown markedly inhibited C/EBP-homologous protein expression and cell apoptosis in the human umbilical vein endothelial cells after hypoxia/reoxygenation treatment. Also, GPR4 blockade attenuated renal injury after IR and reduced the cell apoptosis through the suppression of CHOP expression.

3. Miltz W., et.al. Design and synthesis of potent and orally active GPR4 antagonists with modulatory effects on nociception, inflammation, and angiogenesis. Bioorganic & medicinal chemistry. 2017, 25(16):4512-25. PubMed ID: 28689977
   
   

   This article indicates that GPR4 has a potent cellular activity and is efficacious in animal models of angiogenesis, inflammation, and pain.

4. Ren J., et.al. Human GPR4 and the Notch signaling pathway in endothelial cell tube formation. Molecular medicine reports. 2016, 14(2):1235-40. PubMed ID: 27279286
   
   

   This report indicates that GPR4 could affect endothelial cells by regulating Notch1, a function that may be important for physiological and pathological angiogenesis.

5. Tao S.C., et.al. Decreased extracellular pH inhibits osteogenesis through proton-sensing GPR4-mediated suppression of yes-associated protein. Scientific reports. 2016, 6:26835. PubMed ID: 27256071
   
   

   This article reports that the osteogenic differentiation of bone marrow-derived mesenchymal stem cells (BMSCs) is significantly inhibited by decreases in the extracellular pH. And proton-sensing GPR4 signaling could mediate the proton-induced inhibitory effects on the osteogenesis of BMSCs. It reveals that the extracellular pH could modulate the osteogenic responses of BMSCs by regulating the proton-sensing GPR4-YAP pathway.

GPR4 Preparation Options

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Reference

1. Tobo, et al. (2015). Characterization of imidazopyridine compounds as negative allosteric modulators of proton-sensing GPR4 in extracellular acidification-induced responses. PLoS One. 10.6: e0129334.

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