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The role of Ca²⁺ feedback in shaping InsP₃-evoked Ca²⁺ signals in mouse pancreatic acinar cells

J. F. Kidd, K. E. Fogarty *, R. A. Tuft * and P. Thorn

Cytosolic Ca²⁺ has been proposed to act as both a positive and a negative feedback signal on the inositol trisphosphate (InsP₃) receptor. However, it is unclear how this might affect the Ca²⁺ response in vivo.

Mouse pancreatic acinar cells were whole-cell patch clamped to record the Ca²⁺-dependent chloride (Cl_(Ca)) current spikes and imaged to record the cytosolic Ca²⁺ spikes elicited by the injection of Ins(2,4,5)P₃. Increasing concentrations of Ca²⁺ buffer (up to 200 µM EGTA or BAPTA) were associated with the appearance of steps in the current activation phase and a prevalence of smaller-amplitude Cl_(Ca) spikes. Imaging experiments showed that with increased buffer the secretory pole cytosolic Ca²⁺ signal became fragmented and spatially discrete Ca²⁺ release events were observed.

At higher buffer concentrations (200-500 µM), increasing concentrations of EGTA increased spike frequency and reduced spike amplitude. In contrast, BAPTA decreased spike frequency and maintained large spike amplitudes.

We conclude that, during InsP₃-evoked spiking, long-range Ca²⁺ feedback (~2-4 µm) shapes the rising phase of the Ca²⁺ signal by acting to co-ordinate discrete Ca²⁺ release events and short-range (~40 nm) Ca²⁺ feedback acts to inhibit further Ca²⁺ release.

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