Adaptation by the collecting duct to an exogenous acid load is blunted by deletion of the proton-sensing receptor GPR4

Sun, Xuming; Stephens, Lisa; DuBose, Thomas D.; Petrovic, Snezana

doi:10.1152/ajprenal.00507.2014

Cited by 16 publications

(21 citation statements)

References 99 publications

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“…Surprisingly, GPR4 deletion in mice increases the expression level of calcium-sensing receptor (CASR) by twofold in the kidney, both at baseline and also during acidic challenge. This intriguing finding strengthens the potential involvement of CASR in renal acid-base regulation and tightens the link between systemic calcium and pH homeostasis (Sun et al 2015). In addition, GPR4 expression is also seen in vascular endothelial and smooth muscle cells, brain, lungs, heart and liver , Mahadevan et al 1995, Lum et al 2003, Kim et al 2005, where its functional role is not yet completely understood.…”

Section: Gpr4supporting

confidence: 69%

“…Furthermore, the cell‐type composition of intercalated cells (ICs) in the collecting ducts were also found to be altered in the GPR4 KO mice, with an increased number of A‐ICs and reduced number of B‐ICs and non‐A–non‐B cells in GPR4 KOs compared with WT (Sun et al . ).…”

Section: Gpr4mentioning

confidence: 97%

“…This intriguing finding strengthens the potential involvement of CASR in renal acid–base regulation and tightens the link between systemic calcium and pH homeostasis (Sun et al . ). In addition, GPR4 expression is also seen in vascular endothelial and smooth muscle cells, brain, lungs, heart and liver (An et al .…”

Section: Gpr4mentioning

confidence: 97%

“…This phenotype agrees well with the GPR4 localization in the collecting duct, as it is a major site for acid-base regulation in the kidneys. Furthermore, the cell-type composition of intercalated cells (ICs) in the collecting ducts were also found to be altered in the GPR4 KO mice, with an increased number of A-ICs and reduced number of B-ICs and non-A-non-B cells in GPR4 KOs compared with WT (Sun et al 2015).…”

Section: Gpr4mentioning

confidence: 99%

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Unsung renal receptors: orphan G‐protein‐coupled receptors play essential roles in renal development and homeostasis

Rajkumar

Pluznick

2016

Acta Physiologica

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Recent studies have shown that orphan GPCRs of the GPR family are utilized as specialized chemosensors in various tissues to detect metabolites, and in turn to activate downstream pathways which regulate systemic homeostasis. These studies often find that such metabolites are generated by well-known metabolic pathways, implying that known metabolites and chemicals may perform novel functions. In this review, we summarize recent findings highlighting the role of deorphanized GPRs in renal development and function. Understanding the role of these receptors is critical in gaining insights into mechanisms that regulate renal function both in health and in disease.

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Section: Gpr4supporting

confidence: 69%

Section: Gpr4mentioning

confidence: 97%

Section: Gpr4mentioning

confidence: 97%

Section: Gpr4mentioning

confidence: 99%

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Unsung renal receptors: orphan G‐protein‐coupled receptors play essential roles in renal development and homeostasis

Rajkumar

Pluznick

2016

Acta Physiologica

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“…; Sun et al. , ), and round ray gill acid‐ and base‐secreting cells contain both sAC and tmACs (Roa and Tresguerres ). The existence of multiple sources of cAMP raises questions about how downstream signaling is regulated and coordinated.…”

Section: Introductionmentioning

confidence: 99%

Bicarbonate‐sensing soluble adenylyl cyclase is present in the cell cytoplasm and nucleus of multiple shark tissues

Roa

Tresguerres

2017

Physiological Reports

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The enzyme soluble adenylyl cyclase (sAC) is directly stimulated by bicarbonate (HCO3 −) to produce the signaling molecule cyclic adenosine monophosphate (cAMP). Because sAC and sAC‐related enzymes are found throughout phyla from cyanobacteria to mammals and they regulate cell physiology in response to internal and external changes in pH, CO2, and HCO3 −, sAC is deemed an evolutionarily conserved acid‐base sensor. Previously, sAC has been reported in dogfish shark and round ray gill cells, where they sense and counteract blood alkalosis by regulating the activity of V‐type H+‐ ATPase. Here, we report the presence of sAC protein in gill, rectal gland, cornea, intestine, white muscle, and heart of leopard shark Triakis semifasciata. Co‐expression of sAC with transmembrane adenylyl cyclases supports the presence of cAMP signaling microdomains. Furthermore, immunohistochemistry on tissue sections, and western blots and cAMP‐activity assays on nucleus‐enriched fractions demonstrate the presence of sAC protein in and around nuclei. These results suggest that sAC modulates multiple physiological processes in shark cells, including nuclear functions.

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Physiological relevance of proton-activated GPCRs

Silva

Wagner

2022

Pflugers Arch - Eur J Physiol

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The detection of H+ concentration variations in the extracellular milieu is accomplished by a series of specialized and non-specialized pH-sensing mechanisms. The proton-activated G protein–coupled receptors (GPCRs) GPR4 (Gpr4), TDAG8 (Gpr65), and OGR1 (Gpr68) form a subfamily of proteins capable of triggering intracellular signaling in response to alterations in extracellular pH around physiological values, i.e., in the range between pH 7.5 and 6.5. Expression of these receptors is widespread for GPR4 and OGR1 with particularly high levels in endothelial cells and vascular smooth muscle cells, respectively, while expression of TDAG8 appears to be more restricted to the immune compartment. These receptors have been linked to several well-studied pH-dependent physiological activities including central control of respiration, renal adaption to changes in acid–base status, secretion of insulin and peripheral responsiveness to insulin, mechanosensation, and cellular chemotaxis. Their role in pathological processes such as the genesis and progression of several inflammatory diseases (asthma, inflammatory bowel disease), and tumor cell metabolism and invasiveness, is increasingly receiving more attention and makes these receptors novel and interesting targets for therapy. In this review, we cover the role of these receptors in physiological processes and will briefly discuss some implications for disease processes.

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Adaptation by the collecting duct to an exogenous acid load is blunted by deletion of the proton-sensing receptor GPR4

Abstract: Sun X, Stephens L, DuBose TD Jr., Petrovic S. Adaptation by the collecting duct to an exogenous acid load is blunted by deletion of the proton-sensing receptor GPR4.

Cited by 16 publications

References 99 publications

Unsung renal receptors: orphan G‐protein‐coupled receptors play essential roles in renal development and homeostasis

Unsung renal receptors: orphan G‐protein‐coupled receptors play essential roles in renal development and homeostasis

Bicarbonate‐sensing soluble adenylyl cyclase is present in the cell cytoplasm and nucleus of multiple shark tissues

Physiological relevance of proton-activated GPCRs

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