PubMed · 11593375
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W A Silverman. 2001. ROP--forme fruste.. https://doi.org/10.1038/sj.jp.7210558
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ACTH is the major regulator of adrenal cortex function, having acute and chronic effects on steroid synthesis and secretion. The precise molecular mechanisms by which ACTH stimulates steroid synthesis and secretion, as well as cell hypertrophy, survival, and migration are still poorly understood. Several studies have shown that ACTH action is mediated not only by cyclic adenosine monophosphate (cAMP), but also by calcium (Ca(2+)), both interacting closely through positive feedback loops to enhance steroid secretion. However, in spite of the evidence that ACTH could stimulate other signaling pathways, such as inositol phosphates and diacylglycerol or mitogenic-activated protein kinase pathway (MAPK), none is as potent as cAMP. Recent data indicate that duration and potency of the cAMP production could be modulated by several isoforms of adenylyl cyclases and phosphodiesterases. In addition, calcium is probably not a first second messenger per se; rather, there are several arguments indicating that its increase occurs following cAMP production. Finally, in addition to steroid secretion, ACTH, through cAMP, is a survival factor, protecting cells against apoptosis. All of the effects of ACTH are dependent on cytoskeleton integrity. In summary, after 30 years of intensive research in this field, cAMP remains the first obligatory second messenger of ACTH action. However, recent work emphasizes that cell environment (matrix and cytoskeleton) probably interacts with cAMP to coordinate functions other than steroid secretion.
We studied the effect of the adrenocorticotropin hormone (ACTH) on the expression of the steroidogenic acute regulatory protein (StAR) in vivo in rat and hamster adrenals and also in transfection experiments using COS-1 cells. In vivo, ACTH increased the level of StAR mRNA within 30-60 minutes and also increased the quantity of StAR, but with a 2-3-hour delay. ACTH induced the formation of many acidic StAR species as analyzed by two-dimensional gel electrophoresis and immunoblotting. In the transfection experiments, (Bu)(2)-cAMP also induced the formation of many acidic species for the hamster StAR; in COS-1 cells, StAR is phosphorylated mainly on serine (S) residue(s). When alanine (A) was substituted for serine, S13A, S185A, and S194A mutants had decreased StAR activity compared to wildtype, thus determining the importance of these amino acid residues in StAR action. The full-length WT, N46-truncated StAR lacking its mitochondrial import sequence, and N46-S194A had similar activities, whereas N46-S185A had completely lost its activity. Our results suggest that S194, but not S185, functions in association with the mitochondrial import sequence for the initiation of StAR activation. Further studies showed that S185 is implicated in salt bridge stability, not in StAR phosphorylation, suggesting its importance for StAR folding. Thermodynamic calculations of the hamster StAR homology model based on MLN64 show that StAR can partially unfold to bind cholesterol and serve as a rapid transfer mechanism for eventual translocation into mitochondria. This is supportive of a StAR functioning either outside the mitochondria or in the mitochondrial intermembrane space.
The present study was undertaken to evaluate the effects of melatonin (MT) on spleen lymphocyte proliferation and release of pituitary pro-opiomelanocortin (POMC)-derived peptides in surgically traumatized rats. MT prevented the depression of lymphocyte proliferation induced by trauma in vivo and in vitro, and prevented the decrease of beta-endorphin and adrenocorticotropin in the pituitary in vivo, but dose-dependently inhibited the release of POMC-derived peptides from the pituitary in vitro. The culture media of the pituitaries derived from the traumatized rats inhibited lymphocyte proliferation of normal rats. These results suggest that MT can improve the trauma-induced depression of lymphocyte proliferation and inhibit the release of POMC-derived peptides. The neuroimmunomodulatory role of MT and POMC-derived peptides deserves further study.