Search

The plasma membrane of parotid acinar cells is functionally divided into apical and basolateral regions. According to the current model, fluid secretion is driven by transepithelial ion gradient, which facilitates water movement by osmosis into the acinar lumen from the interstitium. The osmotic gradient is created by the apical Cl− efflux and the subsequent paracellular Na+ transport. In this model, the Na+-K+ pump is located exclusively in the basolateral membrane and has essential role in salivary secretion, since the driving force for Cl− transport via basolateral Na+-K+-2Cl− cotransport is generated by the Na+-K+ pump. In addition, the continuous electrochemical gradient for Cl− flow during acinar cell stimulation is maintained by the basolateral K+ efflux. However, using a combination of single-cell electrophysiology and Ca2+-imaging, we demonstrate that photolysis of Ca2+ close to the apical membrane of parotid acinar cells triggered significant K+ current, indicating that a substantial amount of K+ is secreted into the lumen during stimulation. Nevertheless, the K+ content of the primary saliva is relatively low, suggesting that K+ might be reabsorbed through the apical membrane. Therefore, we investigated the localization of Na+-K+ pumps in acinar cells. We show that the pumps appear evenly distributed throughout the whole plasma membrane, including the apical pole of the cell. Based on these results, a new mathematical model of salivary fluid secretion is presented, where the pump reabsorbs K+ from and secretes Na+ to the lumen, which can partially supplement the paracellular Na+ pathway. [ABSTRACT FROM AUTHOR]

We develop a mathematical model of a salivary gland acinar cell with the objective of investigating the role of two Cl-/HCO3- exchangers from the solute carrier family 4 (Slc4), Ae2 (Slc4a2) and Ae4 (Slc4a9), in fluid secretion. Water transport in this type of cell is predominantly driven by Cl- movement. Here, a basolateral Na+/K+ adenosine triphosphatase pump (NaK-ATPase) and a Na+–K+–2Cl- cotransporter (Nkcc1) are primarily responsible for concentrating the intracellular space with Cl- well above its equilibrium potential. Gustatory and olfactory stimuli induce the release of Ca2+ ions from the internal stores of acinar cells, which triggers saliva secretion. Ca2+-dependent Cl- and K+ channels promote ion secretion into the luminal space, thus creating an osmotic gradient that promotes water movement in the secretory direction. The current model for saliva secretion proposes that Cl-/HCO3- anion exchangers (Ae), coupled with a basolateral Na+/proton (H+) (Nhe1) antiporter, regulate intracellular pH and act as a secondary Cl- uptake mechanism (Nauntofte in Am J Physiol Gastrointest Liver Physiol 263(6):G823–G837, 1992; Melvin et al. in Annu Rev Physiol 67:445–469, 2005. 10.1146/annurev.physiol.67.041703.084745). Recent studies demonstrated that Ae4 deficient mice exhibit an approximate 30% decrease in gland salivation (Peña-Münzenmayer et al. in J Biol Chem 290(17):10677–10688, 2015). Surprisingly, the same study revealed that absence of Ae2 does not impair salivation, as previously suggested. These results seem to indicate that the Ae4 may be responsible for the majority of the secondary Cl- uptake and thus a key mechanism for saliva secretion. Here, by using ‘in-silico’ Ae2 and Ae4 knockout simulations, we produced mathematical support for such controversial findings. Our results suggest that the exchanger’s cotransport of monovalent cations is likely to be important in establishing the osmotic gradient necessary for optimal transepithelial fluid movement. [ABSTRACT FROM AUTHOR]

Key points Agonist-dependent oscillations in the concentration of free cytosolic calcium are a vital mechanism for the control of airway smooth muscle contraction and thus are a critical factor in airway hyper-responsiveness., Using a mathematical model, closely tied to experimental work, we show that the oscillations in membrane potential accompanying the calcium oscillations have no significant effect on the properties of the calcium oscillations., In addition, the model shows that calcium entry through store-operated calcium channels is critical for calcium oscillations, but calcium entry through voltage-gated channels has much less effect., The model predicts that voltage-gated channels are less important than store-operated channels in the control of airway smooth muscle tone., Abstract Airway smooth muscle contraction is typically the key mechanism underlying airway hyper-responsiveness, and the strength of muscle contraction is determined by the frequency of oscillations of intracellular calcium (Ca2+) concentration. In airway smooth muscle cells, these Ca2+ oscillations are caused by cyclic Ca2+ release from the sarcoplasmic reticulum, although Ca2+ influx via plasma membrane channels is also necessary to sustain the oscillations over longer times. To assess the relative contributions of store-operated and voltage-gated Ca2+ channels to this Ca2+ influx, we generated a comprehensive mathematical model, based on experimental Ca2+ measurements in mouse precision-cut lung slices, to simulate Ca2+ oscillations and changes in membrane potential. Agonist-induced Ca2+ oscillations are accompanied by oscillations in membrane potential, although the membrane potential oscillations are too small to generate large Ca2+ currents through voltage-gated Ca2+ channels, and thus have little effect on the Ca2+ oscillations. Ca2+ entry through voltage-gated channels only becomes important when the cell is depolarized (e.g. by a high external K+ concentration). As a result, agonist-induced Ca2+ oscillations are critically dependent on Ca2+ entry through store-operated channels but do not depend strongly on Ca2+ entry though voltage-gated channels. [ABSTRACT FROM AUTHOR]

Oscillations in the concentration of free cytosolic Ca2+ are an important and ubiquitous control mechanism in many cell types. It is thus correspondingly important to understand the mechanisms that underlie the control of these oscillations and how their period is determined. We show that Class I Ca2+ oscillations (i.e., oscillations that can occur at a constant concentration of inositol trisphosphate) have a common dynamical structure, irrespective of the oscillation period. This commonality allows the construction of a simple canonical model that incorporates this underlying dynamical behavior. Predictions from the model are tested, and confirmed, in three different cell types, with oscillation periods ranging over an order of magnitude. The model also predicts that Ca2+ oscillation period can be controlled by modulation of the rate of activation by Ca2+ of the inositol trisphosphate receptor. Preliminary experimental evidence consistent with this hypothesis is presented. Our canonical model has a structure similar to, but not identical to, the classic FitzHugh–Nagumo model. The characterization of variables by speed of evolution, as either fast or slow variables, changes over the course of a typical oscillation, leading to a model without globally defined fast and slow variables. [ABSTRACT FROM AUTHOR]