Ca2+ signaling and exocytosis in pituitary corticotropes.

Abstract: The secretion of adrenocorticotrophin (ACTH) from corticotropes is a key component in the endocrine response to stress. The resting potential of corticotropes is set by the basal activities of TWIK-related K⁺ (TREK)-1 channel. Corticotrophin-releasing hormone (CRH), the major ACTH secretagogue, closes the background TREK-1 channels via the cAMP-dependent pathway, resulting in depolarization and a sustained rise in cytosolic [Ca²⁺] ([Ca²⁺]_i). By contrast, arginine vasopressin and norepinephrine evoke Ca²⁺ release from the inositol trisphosphate (IP₃)-sensitive store, resulting in the activation of small conductance Ca²⁺-activated K⁺ channels and hyperpolarization. Following [Ca²⁺]_i rise, cytosolic Ca²⁺ is taken into the mitochondria via the uniporter. Mitochondrial inhibition slows the decay of the Ca²⁺ signal and enhances the depolarization-triggered exocytotic response. Both voltage-gated Ca²⁺ channel activation and intracellular Ca²⁺ release generate spatial Ca²⁺ gradients near the exocytic sites such that the local [Ca²⁺] is ∼3-fold higher than the average [Ca²⁺]_i. The stimulation of mitochondrial metabolism during the agonist-induced Ca²⁺ signal and the robust endocytosis following stimulated exocytosis enable corticotropes to maintain sustained secretion during the diurnal ACTH surge. Arachidonic acid (AA) which is generated during CRH stimulation activates TREK-1 channels and causes hyperpolarization. Thus, corticotropes may regulate ACTH release via an autocrine feedback mechanism. [Copyright &y& Elsevier]