Extracellular pH in Restricted Domains as a Gating Signal for Ion Channels Involved in Transepithelial Transport

Abstract

The importance of intracellular pH (pH i ) in the regulation of diverse cellular activities ranging from cell proliferation and differentiation to cell cycle, migration and apoptosis has long been recognised. More recently, extracellular pH (pH o ), in particular that of relatively inaccessible compartments or domains that occur between cells in tissues, has begun to be acknowledged as a relevant signal in cell regulation. This should not be surprising given the abundant reports highlighting the pH o -dependence of the activity of membrane proteins facing the extracellular space such as receptors, transporters, ion channels and enzymes. Changes in pH affect the ionisation state of proteins through the effect on their titratable groups. There are proteins, however, which respond to pH shifts with conformational changes that are crucial for catalysis or transport activity. In such cases protons act as signalling molecules capable of eliciting fast and localised responses. We provide examples of ion channels that appear fastidiously designed to respond to extracellular pH in a manner that suggests specific functions in transporting epithelia. We shall also present ideas as to how these channels participate in complex transepithelial transport processes and provide preliminary experiments illustrating a new way to gauge pH o in confined spaces of native epithelial tissue.

Proinflammatory cytokine secretion is suppressed by TMEM16A or CFTR channel activity in human cystic fibrosis bronchial epithelia

“…Considering that the CFTR suppressor effect was restricted to respiratory epithelia cultured under ALC but not LLC, it is conceivable that besides ionic or compositional changes, physicochemical alterations (e.g., surface tension, osmotic and oxidoreductive state) of the ASL and/or the apical PM may constitute upstream signaling for IL-8 secretion. Among other factors, signal transduction pathways involved could be modulated by ion channel and receptor protein kinase or phosphatase functions affected by changes in the membrane potential and pH (Bocharov et al ., 2008; Sandoval et al ., 2011), as well as by the oxidoreductive state of the ASL (Blanchetot et al ., 2002). The supraproportional effect of few individual wt CFTR-expressing cells on the IL-8 secretion by CFBE cells in mixed populations, as well as in transduced primary HBE cultures, suggests that an average reduction in the anion transport capacity at the apical membrane leads to global changes in signaling of epithelial sheets.…”

K2P TASK‐2 and KCNQ1–KCNE3 K+ channels are major players contributing to intestinal anion and fluid secretion

“…; Sandoval et al . ). Figure A shows the transgene used to generate the Tg(Kcne3‐D90N) transgenic animals.…”

Does pH of tyrode solution modify glucose and electrolyte jejunal absorption in rats?

“…Recent studies suggest that changes in extracellular pH affect the ionization state of membrane proteins includeing transporters and ion channels with specific functions in transporting epithelia [4]. The surface pH of rat intestine had been measured in vivo, confirming the phenomenon of acidification in the jejunum followed by an alkalinization process in the ileum [5].…”