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Dominant Role of Mitochondria in Calcium Homeostasis of Single Rat Pituitary Corticotropes

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 rise in cytosolic free Ca²⁺ concentration ([Ca²⁺]_i) is the major trigger for secretion of ACTH from pituitary corticotropes. To better understand the shaping of the Ca²⁺ signal in corticotropes, we investigated the mechanisms regulating the depolarization-triggered Ca²⁺ signal using patch-clamp techniques and indo-1 fluorometry. The rate of cytosolic Ca²⁺ clearance was unaffected by inhibitors of Na⁺/Ca²⁺ exchanger or plasma membrane Ca²⁺-ATPase (PMCA), slightly slowed by sarco-endoplasmic reticulum Ca²⁺-ATPase (SERCA) inhibitor, but dramatically slowed by mitochondrial uncouplers or inhibitor of mitochondrial uniporter. Measurements with rhod-2 revealed that depolarization-triggered increase in mitochondrial Ca²⁺ concentration. Thus, mitochondria have a dominant role in cytosolic Ca²⁺ clearance. Using the Mn²⁺ quench technique, we found the presence of a continuous basal Ca²⁺ influx in corticotropes. This basal Ca²⁺ influx was balanced by the combined actions of mitochondrial uniporter and PMCA and SERCA pumps. Inhibition of the mitochondrial uniporter or PMCA or SERCA pumps elevated basal [Ca²⁺]_i. Using membrane capacitance measurement, we found that the change in the shape of the depolarization-triggered Ca²⁺ signal after mitochondrial inhibition was associated with enhancement of the exocytotic response. Thus, mitochondria have a dominant role in the regulation of Ca²⁺ signal and exocytosis in corticotropes.

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