Regulation of H+ and HCO3- transport proteins in salivary glands in health and disease
Final Report Abstract
Changes in systemic acid-base homeostasis cause a series of organ-specific cellular responses, among them changes of acid-base transporter activities by recruitment of the transporters towards to or away from the plasma membrane. The aims of the project were: 1) to identify the mechanisms that control the regulation of the key proton and bicarbonate transporters V-ATPase, NBCe1-A, and NBCe1-B under physiological conditions and following acid-base disturbances, 2) to understand the biological significance of transporter traffic in regulation of intracellular pH and bicarbonate transport, and 3) to elucidate the underlying molecular basis of transporter redistribution. The results obtained from our work have demonstrated that three different cellular populations whose function is associated either with bicarbonate transport or with changes of extracellular pH, i.e. renal proximal tubule cells, duct cells of the submandibular gland (SMG), and hippocampal neurons, are equipped with a similar set of acid-base transporters, such as V-ATPase, NBCe1-A, and NBCe1-B. The data have also shown that following systemic acid-base perturbations proton and bicarbonate transporters are not regulated at the transcriptional or translational level. In fact, translocation of acid-base transporters from intracellular pools to the plasma membrane is an early mechanism activated for cells to cope with acid-base changes and serves the regulation of intracellular pH. However, the response of epithelia to systemic acid-base changes reflects their specialized functions and consists of differential recruitment pattern of proton and bicarbonate transporters. In addition, the mechanisms underlying individual transporter trafficking are distinct. We have provided first evidence that Rab GTPases play a critical role on transporter trafficking and introduced Rab11b as a crucial regulator and Rip11 as mediator of acidosis-induced V-ATPase traffic in SMG, and Rab8a as mediator of acidosis-induced NBCe1-A translocation in hippocampal neurons. We have further identified the signalling pathway sAC/PKA/CREB as a molecular cascade upstream of Rab11b. We propose that sAC/PKA pathway represents an early response of SMG cells to acid load and initiates acidosis-induced V-ATPase trafficking via regulation of Rab11b expression, followed by activation of ERK signaling to sustain adaptive response of SMG cells. In contrast, acidosis-induced NBCe1-A trafficking is mainly controlled by Src/ERK signalling. These data have provided important insights in the molecular network underlying acid-base transporter trafficking as response to changes of systemic or local pH homeostasis by identifying novel molecular parameters. The unravelled mechanisms could account not only for acid-base transporter-specific redistribution in epithelia, but also for accumulation and activity of transporters in other cellular systems as well.
Publications
- (2007). Adaptive redistribution of NBCe1-A and NBCe1-B in rat kidney proximal tubule and striated ducts of salivary glands during acid-base disturbances. Am J Physiol-Regul Integr Comp Physiol 293: R2400-R2411
Brandes, A., Oehlke, O., Schümann, A., Heidrich, S., Thévenod, F., Roussa, E.
- (2011). Rab11b regulates trafficking of V- ATPase in salivary ducts during acid-base disturbances. J Cell Physiol 226: 638-651
Oehlke O, Martin H, Osterberg N, Roussa E
- (2012). Acidosis-induced V-ATPase trafficking in salivary ducts is initiated by cAMP/PKA/CREB pathway via regulation of Rab11b expression. Int J Biochem Cell Biol 44: 1254-1265
Oehlke O, Schlosshardt C, Feuerstein M, Roussa E
(See online at https://doi.org/10.1016/j.biocel.2012.04.018)
