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Cytosolic Ca²⁺ and Ca²⁺-activated Cl^- current dynamics: insights from two functionally distinct mouse exocrine cells

David R. Giovannucci, Jason I. E. Bruce, Stephen V. Straub, Jorge Arreola, James Sneyd *, Trevor J. Shuttleworth and David I. Yule

The dynamics of Ca²⁺ release and Ca²⁺-activated Cl^- currents in two related, but functionally distinct exocrine cells, were studied to gain insight into how the molecular specialization of Ca²⁺ signalling machinery are utilized to produce different physiological endpoints: in this case, fluid or exocytotic secretion. Digital imaging and patch-clamp methods were used to monitor the temporal and spatial properties of changes in cytosolic Ca²⁺ concentration ([Ca²⁺]_c) and Cl^- currents following the controlled photolytic release of caged-InsP₃ or caged-Ca²⁺. In parotid and pancreatic acinar cells, changes in [Ca²⁺]_c and activation of a Ca²⁺-activated Cl^- current occurred with close temporal coincidence. In parotid, a rapid global Ca²⁺ signal was invariably induced, even with low-level photolytic release of threshold amounts of InsP₃. In pancreas, threshold stimulation generated an apically delimited [Ca²⁺]_c signal, while a stronger stimulus induced a global [Ca²⁺]_c signal which exhibited characteristics of a propagating wave. InsP₃ was more effective in parotid, where [Ca²⁺]_c signals initiated with shorter latency and exhibited a faster time-to-peak than in pancreas. The increased potency of InsP₃ in parotid probably results from a four-fold higher number of InsP₃ receptors as measured by radiolabelled InsP₃ binding and western blot analysis. The Ca²⁺ sensitivity of the Cl^- channels in parotid and pancreas was determined from the [Ca²⁺]-current relationship measured during a dynamic 'Ca²⁺ ramp' produced by the continuous, low-level photolysis of caged-Ca²⁺. In addition to a greater number of InsP₃ receptors, the Cl^- current density of parotid acinar cells was more than four-fold greater than that of pancreatic cells. Whereas activation of the current was tightly coupled to increases in Ca²⁺ in both cell types, local Ca²⁺ clearance was found to contribute substantially to the deactivation of the current in parotid. These data reveal specializations of common modules of Ca²⁺-release machinery and subsequent effector activation that are specifically suited to the distinct functional roles of these two related cell types.

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