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.
Published Version
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