Biochemical and Ionic signaling mechanisms for ACTH-stimulated cortisol production

Abstract

Adrenocorticotropic hormone (ACTH)-stimulated cortisol production by adrenal zona fasciculata cells requires coordinated biochemical and ionic signaling mechanisms that employ adenosine 3', 5'-cyclic monophosphate (cAMP) and Ca(2+) as intracellular messengers. As the primary messenger generated in response to ACTH receptor activation, cAMP acts at multiple sites to produce the full steroidogenic response that includes both rapid and delayed components. Biochemically, cAMP activates and induces the expression of multiple proteins that function in converting cholesterol to cortisol. These include the steroid acute regulatory (StAR) protein as well as steroidogenic enzymes. cAMP also inhibits a background K(+) channel (bTREK-1), which sets the resting potential of adrenal zona fasciculata (AZF) cells, thereby triggering membrane depolarization and Ca(2+) entry through voltage-gated Ca(2+) channels. Ca(2+) also accelerates the production of cortisol from cholesterol by activating or inducing the synthesis of steroidogenic proteins. In this scheme, background K(+) channels act pivotally by transducing a hormonal signal at the cell membrane to an ionic signal, leading to depolarization-dependent Ca(2+) entry. In this way, ACTH receptor activation increases cAMP and Ca(2+) in the AZF cell, yielding the full steroidogenic response. In addition to acutely regulating the activity of AZF cell ion channels, ACTH and cAMP also regulate the expression of genes coding for these ion channels. The tonic control of the expression of AZF cell ion channels through the hypothalamic-pituitary-adrenal axis suggests that prolonged stimulation of the AZF cell by ACTH may alter the electrical properties of these cells in a manner which matches the organism's requirement for cortisol.