Regulation of luminal acidification in the male reproductive tract <i>via</i> cell–cell crosstalk

Shum, Winnie; Silva, Nicolas Da; Brown, Dennis; Breton, Sylvie

doi:10.1242/jeb.027284

Cited by 123 publications

(118 citation statements)

References 89 publications

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“…Under physiological conditions, urine pH in the distal tubules and bladder can fall below 5.5 due to the reabsorption of bicarbonate and secretion of hydrogen ions (46). In the skin, acidity plays essential roles in stratum corneum integrity and cohesion, epidermal permeability barrier and antimicrobial barrier function (47)(48)(49); in the epididymis, luminal acidification is essential for sperm maturation and storage (50). In pathological contexts, severe tissue ischemia causes extracellular acidosis (51), inflammation could induce interstitial acidification resulting in decreased extracellular pH values (52,53), and tumor-associated microenvironments are more acidic than normal tissues due to hypoxia, increased glucose metabolism, and ineffective removal of the acidic metabolites.…”

Section: Discussionmentioning

confidence: 99%

Matriptase Activation, an Early Cellular Response to Acidosis

Tseng

Chou

et al. 2010

Journal of Biological Chemistry

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Extracellular acidosis often rapidly causes intracellular acidification, alters ion channel activities, and activates G proteincoupled receptors. In this report, we demonstrated a novel cellular response to acidosis: induction of the zymogen activation of matriptase. Acid-induced matriptase activation is ubiquitous among epithelial and carcinoma cells and is characterized by rapid onset, fast kinetics, and the magnitude of activation seen. Trace amounts of activated matriptase can be detected 1 min after cells are exposed to pH 6.0 buffer, and the vast majority of latent matriptase within the cells is converted to activated matriptase within 20 min. Matriptase activation may be a direct response to proton exposure because acid-induced matriptase activation also occurs in an in vitro, cell-free setting in which intracellular signaling molecules and ion channel activities are largely absent. Acid-induced matriptase activation takes place both on the cell surface and inside the cells, likely due to the parallel intracellular acidification that activates intracellular matriptase. Following matriptase activation, the active enzyme is immediately inhibited by binding to hepatocyte growth factor activator inhibitor 1, resulting in stable matriptase-hepatocyte growth factor activator inhibitor 1 complexes that are rapidly secreted. As an early response to acidosis, matriptase activation can also be induced by perturbation of intracellular pH homeostasis by 5-(N-methyl-N-isobutyl)-amiloride and 5-(N-ethyl-Nisopropyl)-amiloride, both of which inhibit Na ؉ /H ؉ exchangers, and diisothiocyanostilbene-2,2-disulfonic acid, which can inhibit other acid-base ion channels. This study uncovers a novel mechanism regulating proteolysis in epithelial and carcinoma cells, and also demonstrates that a likely function of matriptase is as an early response to acidosis.Matriptase, a type 2 transmembrane serine protease, is broadly expressed by epithelial and carcinoma cells (1-3), and plays essential roles in the maintenance of epithelial integrity, particularly for epidermal terminal differentiation and barrier function (4 -6). A rare human inherited genetic disorder, autosomal recessive ichthyosis, is associated with two missense mutations of the human ST14 gene, which encodes matriptase (7,8). In addition, the protease can exhibit potent oncogenic activity via ras-dependent and ras-independent pathways when it is even slightly overexpressed in the skin of transgenic mice (9). Several tumor xenograft models also provide further evidence that matriptase is strongly associated with cancer cell proliferation, invasion, and metastasis (10, 11). As is typical for classical serine proteases, matriptase is synthesized as a zymogen and must undergo activation by cleavage at Arg 614 (R2VVGG) to gain full proteolytic activity. It is the activity of the mature enzyme that is believed to be responsible for both the physiological and pathological functions of the enzyme identified by studies of animal models and human genetics (12)(13)(14).In contr...

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Section: Discussionmentioning

confidence: 99%

Matriptase Activation, an Early Cellular Response to Acidosis

Tseng

Chou

et al. 2010

Journal of Biological Chemistry

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“…ϩ -ATPases (V-ATPases) 5 are a family of ATP-driven proton pumps that are ubiquitously expressed in eukaryotes and are present in both intracellular compartments and the plasma membrane (1)(2)(3). Acidification of intracellular compartments by V-ATPases is necessary for many pH-dependent cellular processes, including receptor-mediated endocytosis, intracellular trafficking, protease activation, and proton coupled transport of small molecules, such as neurotransmitters (1).…”

Section: The Vacuolar Hmentioning

confidence: 99%

“…Acidification of intracellular compartments by V-ATPases is necessary for many pH-dependent cellular processes, including receptor-mediated endocytosis, intracellular trafficking, protease activation, and proton coupled transport of small molecules, such as neurotransmitters (1). Plasma membrane V-ATPases also serve diverse functions, including urinary acidification, bone resorption, sperm maturation, and cancer cell invasion (3)(4)(5)(6). Altered functioning of V-ATPases has therefore been implicated in many human disease states, including osteoporosis, renal disease, and cancer.…”

Section: The Vacuolar Hmentioning

confidence: 99%

Structural Analysis of the N-terminal Domain of Subunit a of the Yeast Vacuolar ATPase (V-ATPase) Using Accessibility of Single Cysteine Substitutions to Chemical Modification

Liberman

Cotter

Baleja

et al. 2013

Journal of Biological Chemistry

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Background:The N terminus of the V-ATPase subunit a functions in intracellular targeting and regulation of assembly.Results: A homology model of this domain was tested by determining aqueous accessibility of introduced cysteines. Conclusion:The results identify residues located at the peripheral/integral domain interface. Significance: The identified sites may participate in interactions that regulate V-ATPase assembly.

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“…In the epididymis, the physiological role of this mechanism is to maintain the lumen at the low pH that is necessary for sperm maturation and storage. In the same epithelium, epididymal principal cells secrete bicarbonate during sexual arousal to activate sperm (122,124). Proton secretion by clear cells balances this alkalinization, and restores luminal pH to its resting acidic state.…”

Section: Regulation Of Proton Secretion By Soluble Adenylyl Cyclase: mentioning

confidence: 99%

New insights into the dynamic regulation of water and acid-base balance by renal epithelial cells

Brown

Bouley

Păunescu

et al. 2012

American Journal of Physiology-Cell Physiology

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Maintaining tight control over body fluid and acid-base homeostasis is essential for human health and is a major function of the kidney. The collecting duct is a mosaic of two cell populations that are highly specialized to perform these two distinct processes. The antidiuretic hormone vasopressin (VP) and its receptor, the V2R, play a central role in regulating the urinary concentrating mechanism by stimulating accumulation of the aquaporin 2 (AQP2) water channel in the apical membrane of collecting duct principal cells. This increases epithelial water permeability and allows osmotic water reabsorption to occur. An understanding of the basic cell biology/physiology of AQP2 regulation and trafficking has informed the development of new potential treatments for diseases such as nephrogenic diabetes insipidus, in which the VP/V2R/AQP2 signaling axis is defective. Tubule acidification due to the activation of intercalated cells is also critical to organ function, and defects lead to several pathological conditions in humans. Therefore, it is important to understand how these "professional" proton-secreting cells respond to environmental and cellular cues. Using epididymal proton-secreting cells as a model system, we identified the soluble adenylate cyclase (sAC) as a sensor that detects luminal bicarbonate and activates the vacuolar proton-pumping ATPase (V-ATPase) via cAMP to regulate tubular pH. Renal intercalated cells also express sAC and respond to cAMP by increasing proton secretion, supporting the hypothesis that sAC could function as a luminal sensor in renal tubules to regulate acid-base balance. This review summarizes recent advances in our understanding of these fundamental processes. aquaporin 2; vacuolar ATPase; intercalated cell; principal cell; kidney; epididymis IT HAS BEEN KNOWN FOR MANY years that the major functions of collecting duct principal cells and intercalated cells (Fig. 1) can be regulated by the recycling of aquaporin 2 (AQP2) and the vacuolar H ϩ -ATPase (V-ATPase), respectively, between cytoplasmic vesicles and the plasma membrane (1,26,28,40,54,67,85,142). A considerable amount of the earlier data illuminating these processes was generated using readily accessible model epithelial systems such as the toad urinary bladder (48,83,140) and the turtle bladder (3,127,128), in which cellular function and morphology could be correlated with measurements of water flux and acid-base transport. More recently, a variety of in vitro cell culture models have replaced the toad bladder as an experimental system for water channel trafficking and function. This review will show how cell cultures have provided novel and important information on aquaporin 2 trafficking that has been translatable to the in vivo situation and has allowed the development of strategies to bypass the vasopressin (VP)/vasopressin type 2 receptor (V2R) signaling axis that is defective in nephrogenic diabetes insipidus (NDI). We will go on to demonstrate how the epididymis and vas deferens (from the male reproductive tract) ha...

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Regulation of luminal acidification in the male reproductive tract via cell–cell crosstalk

Cited by 123 publications

References 89 publications

Matriptase Activation, an Early Cellular Response to Acidosis

Matriptase Activation, an Early Cellular Response to Acidosis

Structural Analysis of the N-terminal Domain of Subunit a of the Yeast Vacuolar ATPase (V-ATPase) Using Accessibility of Single Cysteine Substitutions to Chemical Modification

New insights into the dynamic regulation of water and acid-base balance by renal epithelial cells

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