IRR is expressed in stomach enterochromaffin-like cells ( 54) and in kidney B-type intercalated cells ( 55). IRR activation is reversible, dose dependent, and mediated via the N-terminal extracellular domains. These proteins are inactive at pH e > 7.5, whereas at pH e 7.9 ( 53). Three GPCRs-GPR4 (also known as GPRC6.1), OGR1 (ovarian cancer GPCR1, also known as GPR68), and TDAG8 (T cell death–associated gene 8, also known as GPR65)-are activated by increases in extracellular H + (i.e., decreases in pH e).
In this review, we detail current knowledge of mammalian pH e and pH i sensors ( Figure 1).Ĭells can use a family of H +-sensing G protein–coupled receptors (GPCRs), a number of different types of H +-sensitive ion channels, and an alkali-sensing receptor tyrosine kinase to sense pH e to maintain acid-base balance, to adjust metabolism to environmental conditions, and/or to respond to stresses or sensory stimuli. pH e can be sensed directly (i.e., via protonation of extracellular domains) or can be translated into a pH gradient that is sensed via pH i sensors.
pH e must also be sensed by cells within organs that purposely define local pH gradients (e.g., clear cells of the epididymis, osteoclasts in bone, acid-base-producing cells in the gut and pancreas). Specialized cells within these organs (e.g., alpha- and beta-intercalated cells in the kidney) have the ability to sense extracellular pH (pH e) (recently reviewed in Reference 6). In addition to having sensors for pH i, mammals, like other multicellular organisms, have specific organs (i.e., kidney and lungs) that are responsible for maintaining the organism's pH. Therefore, in this review, we summarize the current knowledge of pH sensors in mammalian systems. Thus, although all enzymes, strictly speaking, are sensitive to pH, and many are sensitive to pH fluctuations in a physiologically relevant range, the pH sensors discussed here are defined as the subset of enzymes that are sensitive to physiologically relevant changes in pH and that elicit an appropriate cellular response.Ĭomprehensive reviews on acid-base sensing in bacteria ( 4) and marine organisms ( 5) were recently published. These sensors must sense the fluctuations in pH and translate changes into appropriate cellular responses, either to restore the pH or membrane voltage balance or to mediate some pH-induced changes. These coupled mechanisms have been authoritatively reviewed elsewhere ( 1– 3), but coordinating the flow of H +, and balancing ions, requires sensors. Moving H + results in charge imbalances across cellular membranes, so these H + movements are coupled to transport of other ions to balance the net movement of charge. This CO 2/HCO 3 −/pH equilibrium is the main physiological buffer.Ĭells have multiple mechanisms by which to correct pH imbalances, most simply by removing and importing H + via so-called acid extruders and acid loaders, respectively. Carbonic anhydrases, which are ubiquitous in physiological systems, equilibrate this reaction nearly instantaneously. In aqueous solutions, CO 2 equilibrates with bicarbonate (HCO 3 −) and a proton (H +) thus, CO 2 generation constantly impacts pH. Cells can be subjected to pH changes in their environment (e.g., in the gut and kidneys and following pathophysiological events such as ischemia), and all cells generate carbon dioxide (CO 2) from the metabolism of nutrients. But the pH i of cells is constantly challenged. Therefore, it is absolutely essential for living organisms to maintain consistent intracellular pH (pH i) and organelle-specific pH. The chemical reactions of living organisms are sensitive to pH, and the enzymes that facilitate these biological reactions have pH optima.
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