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Dominant Role of Sarcoendoplasmic Reticulum Ca²⁺-ATPase Pump in Ca²⁺ Homeostasis and Exocytosis in Rat Pancreatic ß-Cells

Department of Pharmacology, University of Alberta, Edmonton, Alberta, Canada T6G 2H7

Address all correspondence and requests for reprints to: Amy Tse, 9-70 Medical Sciences Building, Department of Pharmacology, University of Alberta, Edmonton, Alberta, Canada T6G 2H7. E-mail: amy.tse{at}ualberta.ca.

The exocytosis of insulin-containing granules from pancreatic ß-cells is tightly regulated by changes in cytosolic Ca²⁺ concentration ([Ca²⁺]_i). We investigated the role of the sarcoendoplasmic reticulum Ca²⁺-ATPase (SERCA) pump, Na⁺/Ca²⁺ exchanger, and plasma membrane Ca²⁺-ATPase pump in the Ca²⁺ dynamics of single rat pancreatic ß-cells. When the membrane potential was voltage clamped at –70 mV (in 3 mM glucose at 22 or 35 C), SERCA pump inhibition dramatically slowed (4-fold) cytosolic Ca²⁺ clearance and caused a sustained rise in basal [Ca²⁺]_i via the activation of capacitative Ca²⁺ entry. SERCA pump inhibition increased (1.8-fold) the amplitude of the depolarization-triggered Ca²⁺ transient at approximately 22 C. Inhibition of the Na⁺/Ca²⁺ exchanger or plasma membrane Ca²⁺-ATPase pump had only minor effects on Ca²⁺ dynamics. Simultaneous measurement of [Ca²⁺]_i and exocytosis (with capacitance measurement) revealed that SERCA pump inhibition increased the magnitude of depolarization-triggered exocytosis. This enhancement in exocytosis was not due to the slowing of the cytosolic Ca²⁺ clearance but was closely correlated to the increase in the peak of the depolarization-triggered Ca²⁺ transient. When compared at similar [Ca²⁺]_i with controls, the rise in basal [Ca²⁺]_i during SERCA pump inhibition did not cause any enhancement in the magnitude of the ensuing depolarization-triggered exocytosis. Therefore, we conclude that in rat pancreatic ß-cells, the rapid uptake of Ca²⁺ by SERCA pump limits the peak amplitude of depolarization-triggered [Ca²⁺]_i rise and thus controls the amount of insulin secretion.

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