Function and Signaling of the pH-Sensing G Protein-Coupled Receptors in Physiology and Diseases

Dong, Lixue; Li, Zhigang; Yang, Li V.

doi:10.1007/978-1-4939-1683-2_4

Cited by 6 publications

(11 citation statements)

References 119 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Acidosis is a noxious stressor associated with many pathological conditions such as cancer, ischemia, and inflammation [ 2 , 3 , 4 , 5 , 6 , 7 , 8 , 18 ]. Glycolytic cell metabolism, hypoxia, and defective blood perfusion are the main causes of excessive proton production and accumulation in the affected tissue, resulting in an acidotic tissue microenvironment [ 3 , 6 , 7 , 8 ].…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Acidosis Activates Endoplasmic Reticulum Stress Pathways through GPR4 in Human Vascular Endothelial Cells

Dong

Krewson

Yang

2017

IJMS

Self Cite

View full text Add to dashboard Cite

Acidosis commonly exists in the tissue microenvironment of various pathophysiological conditions such as tumors, inflammation, ischemia, metabolic disease, and respiratory disease. For instance, the tumor microenvironment is characterized by acidosis and hypoxia due to tumor heterogeneity, aerobic glycolysis (the “Warburg effect”), and the defective vasculature that cannot efficiently deliver oxygen and nutrients or remove metabolic acid byproduct. How the acidic microenvironment affects the function of blood vessels, however, is not well defined. GPR4 (G protein-coupled receptor 4) is a member of the proton-sensing G protein-coupled receptors and it has high expression in endothelial cells (ECs). We have previously reported that acidosis induces a broad inflammatory response in ECs. Acidosis also increases the expression of several endoplasmic reticulum (ER) stress response genes such as CHOP (C/EBP homologous protein) and ATF3 (activating transcription factor 3). In the current study, we have examined acidosis/GPR4-induced ER stress pathways in human umbilical vein endothelial cells (HUVEC) and other types of ECs. All three arms of the ER stress/unfolded protein response (UPR) pathways were activated by acidosis in ECs as an increased expression of phosphorylated eIF2α (eukaryotic initiation factor 2α), phosphorylated IRE1α (inositol-requiring enzyme 1α), and cleaved ATF6 upon acidic pH treatment was observed. The expression of other downstream mediators of the UPR, such as ATF4, ATF3, and spliced XBP-1 (X box-binding protein 1), was also induced by acidosis. Through genetic and pharmacological approaches to modulate the expression level or activity of GPR4 in HUVEC, we found that GPR4 plays an important role in mediating the ER stress response induced by acidosis. As ER stress/UPR can cause inflammation and cell apoptosis, acidosis/GPR4-induced ER stress pathways in ECs may regulate vascular growth and inflammatory response in the acidic microenvironment.

show abstract

Section: Discussionmentioning

confidence: 99%

“…Numerous studies have speculated as to the mechanism with which the body perceives, adapts to, and counteracts acidosis [ 4 , 5 , 17 , 18 ]. Reports have highlighted GPR4, a proton sensor that becomes activated by extracellular acidic pH [ 1 , 2 , 19 , 20 , 21 ].…”

Section: Introductionmentioning

confidence: 99%

Acidosis Activates Endoplasmic Reticulum Stress Pathways through GPR4 in Human Vascular Endothelial Cells

Dong

Krewson

Yang

2017

IJMS

Self Cite

View full text Add to dashboard Cite

show abstract

“…This family of receptors is important for pH sensing in normal physiology of the cardiovascular, renal, respiratory, skeletal, immune, endocrine, and nervous systems [3,16,17,20,[24][25][26][27][28][29][30][31][32][33][34][35]. Cells genetically engineered to overexpress the proton-sensing GPCRs have been creatively utilized as a synthetic pH sensor to regulate gene expression in cell culture, bioreactors, and mice in response to pH and CO 2 changes [36].…”

Section: Introductionmentioning

confidence: 99%

GPR4 decreases B16F10 melanoma cell spreading and regulates focal adhesion dynamics through the G13/Rho signaling pathway

Justus

Yang

2015

Experimental Cell Research

Self Cite

View full text Add to dashboard Cite

“…The family of proton-sensing GPCRs include GPR4, GPR65 (TDAG8), and GPR68 (OGR1). GPR65 and GPR68 are predominately expressed in immune cells while GPR4 is expressed in endothelial cells [7,11,16,26]. This family of receptors have only recently been implicated in the regulation of post-ischemic cellular responses and inflammation [16,[39][40][41][42].…”

Section: Discussionmentioning

confidence: 99%

“…Tissue acidosis commonly exists in inflammatory microenvironments [7,11,12,16,26]. However, the involvement of acidosis in endothelial cell (EC) gap formation is largely unknown.…”

Section: Acidosis Promotes Paracellular Gap Formation In Primary Endomentioning

confidence: 99%

The proton-sensing GPR4 receptor regulates paracellular gap formation and permeability of vascular endothelial cells

Krewson

Sanderlin

Marie

et al. 2019

Preprint

Self Cite

View full text Add to dashboard Cite

Tissue acidosis can be a consequence of numerous disease states including stroke, myocardial infarction, limb ischemia, and inflammation. Blood vessels existing in the affected tissues are associated with the progression of acidosis-related diseases. However, the mechanisms by which endothelial cells (ECs) lining the affected blood vessels sense and respond to an acidic microenvironment remain largely unclear. We investigated the functional effects of the proton-sensing G protein-coupled receptor GPR4 in acidosisinduced endothelial inflammation. GPR4 is highly expressed in ECs and known to regulate EC inflammation and endoplasmic reticulum stress responses within acidic microenvironments. Using genetic and pharmacological approaches, we demonstrate that GPR4 activation by acidosis increases EC paracellular gap formation and permeability.We further demonstrate that GPR4-mediated paracellular gap formation is dependent on the Gα12/13 signaling pathway. To assess the functional role of GPR4 in the inflammatory response in vivo, we utilized an acute hindlimb ischemia-reperfusion mouse model. We demonstrate that both genetic deletion and pharmacological inhibition of GPR4 reduce tissue edema, exudate formation, endothelial adhesion molecule expression, and leukocyte infiltration in the inflamed tissue. Collectively, these data suggest GPR4/Gα12/13 signaling mediates acidosis-induced endothelial paracellular gap formation and permeability. This study implicates GPR4 as a candidate therapeutic target for the remediation of inflammation and tissue edema. tissue microenvironment is associated with a wide range of inflammation-associated disease states such as arthritis, inflammatory bowel disease, myocardial infarction, stroke, and limb ischemia. Previous reports note that local pH ranging from 6.0 to 7.0 is common in the microenvironments of inflamed tissues, solid tumors, and ischemic tissues [9][10][11][12].In ischemic disease, one study demonstrated that within 50 minutes of coronary artery occlusion, local tissue extracellular pH decreased from 7.4 to 5.5 in domestic pigs [13].Furthermore, in the tourniquet-induced rabbit limb ischemia model, local tissue pH decreased rapidly within 1 hour and dropped from 7.30 to 6.36 during the 4 hour course of limb ischemia [14]. In summary, an acidic interstitial pH is an inflammatory microenvironmental factor in many pathological conditions and has been demonstrated to modulate tissue, blood vessel, and immune cell functions [9][10][11][12].Cells can sense extracellular acidification through multiple molecular sensors such as acid-sensing ion channels (ASICs), transient receptor potential (TRP), and proton-sensing G protein-coupled receptors (GPCRs) [7,11,15,16]. GPR4 is a member of the proton-sensing GPCR family, which also includes GPR65 (TDAG8) and GPR68 (OGR1) [7,11,[16][17][18]. GPR4 is highly expressed in vascular endothelial cells (ECs) and has been shown to increase the expression of inflammatory cytokines, chemokines, adhesion molecules, and ER stress related genes upon...

show abstract

Function and Signaling of the pH-Sensing G Protein-Coupled Receptors in Physiology and Diseases

Cited by 6 publications

References 119 publications

Acidosis Activates Endoplasmic Reticulum Stress Pathways through GPR4 in Human Vascular Endothelial Cells

Acidosis Activates Endoplasmic Reticulum Stress Pathways through GPR4 in Human Vascular Endothelial Cells

GPR4 decreases B16F10 melanoma cell spreading and regulates focal adhesion dynamics through the G13/Rho signaling pathway

The proton-sensing GPR4 receptor regulates paracellular gap formation and permeability of vascular endothelial cells

Contact Info

Product

Resources

About