Ca2+ signaling and exocytosis in pituitary corticotropes.
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 [Ca(2+)] ([Ca(2+)](i)). By contrast, arginine vasopressin and norepinephrine evoke Ca(2+) release from the inositol trisphosphate (IP(3))-sensitive store, resulting in the activation of small conductance Ca(2+)-activated K(+) channels and hyperpolarization. Following [Ca(2+)](i) rise, cytosolic Ca(2+) is taken into the mitochondria via the uniporter. Mitochondrial inhibition slows the decay of the Ca(2+) signal and enhances the depolarization-triggered exocytotic response. Both voltage-gated Ca(2+) channel activation and intracellular Ca(2+) release generate spatial Ca(2+) gradients near the exocytic sites such that the local [Ca(2+)] is ~3-fold higher than the average [Ca(2+)](i). The stimulation of mitochondrial metabolism during the agonist-induced Ca(2+) 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.
Department of Pharmacology, University of Alberta, Edmonton, Alberta, Canada. amy.tse@ualberta.ca
Amy
A
Tse
Andy K
AK
Lee
Frederick W
FW
Tse
D000818:Animals; D016718:Arachidonic Acid / Q000378:metabolism; D001127:Arginine Vasopressin / Q000378:metabolism; D002118:Calcium / Q000378:metabolism*; D020013:Calcium Signaling; D052680:Corticotrophs / Q000502:physiology*; D003346:Corticotropin-Releasing Hormone / Q000378:metabolism; D004705:Endocytosis; D056966:Excitation Contraction Coupling; D005089:Exocytosis; D025461:Feedback, Physiological; D006801:Humans; D017136:Ion Transport; D009638:Norepinephrine / Q000378:metabolism
D001127:Arginine Vasopressin; D016718:Arachidonic Acid; D003346:Corticotropin-Releasing Hormone; D002118:Calcium; D009638:Norepinephrine