Gamma-melanotropin response to ovine corticotropin releasing factor in normal humans

Plasma [gamma]-melanotropin was measured by a [gamma]3MSH-specific radioimmunoassay before and after a single bolus intravenous infusion of ovine corticotropin releasing factor (oCRF; 0.1 ug/kg) in seven normal men. A significant increase of [gamma]3MSH was observed 15 minutes post-oCRF infusion, which paralleled a similar increase in plasma cortisol. Bel filtration chromatography revealed that the observed increase was attributable to elevations of 9K and 4K forms of [gamma]3MSH immunoreactivity. Affinity chromatography demonstrated that the majority of [gamma]3MSH immunoreactivity in human plasma is glycosylated. As the smaller forms of [gamma]3MSH are felt to have endocrine activity at the adrenal cortex, these changes may be physiologically relevant.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/26714/1/0000264.pd

Signaling interactions in the adrenal cortex

The major physiological stimuli of aldosterone secretion are angiotensin II (AII) and extracellular K+ whereas cortisol production is primarily regulated by corticotrophin (ACTH) in fasciculata cells. AII triggers Ca2+ release from internal stores that is followed by store-operated and voltage-dependent Ca2+ entry whereas K+-evoked depolarisation activates voltage-dependent Ca2+ channels. ACTH acts primarily through the formation of cAMP and subsequent protein phosphorylation by protein kinase A. Both Ca2+ and cAMP facilitate the transfer of cholesterol to mitochondrial inner membrane. The cytosolic Ca2+ signal is transferred into the mitochondrial matrix and enhances pyridine nucleotide reduction. Increased formation of NADH results in increased ATP production whereas that of NADPH supports steroid production. In reality, the control of adrenocortical function is a lot more sophisticated with second messengers crosstalking and mutually modifying each other’s pathways. Cytosolic Ca2+ and cGMP are both capable of modifying cAMP metabolism whilst cAMP may enhance Ca2+ release and voltage-activated Ca2+ channel activity. Besides, mitochondrial Ca2+ signal brings about cAMP formation within the organelle and this further enhances aldosterone production. Maintained aldosterone and cortisol secretion are optimized by the concurrent actions of Ca2+ and cAMP, as exemplified by the apparent synergism of Ca2+ influx (inducing cAMP formation) and Ca2+ release during response to AII. Thus, cross-actions of parallel signal transducing pathways are not mere intracellular curiosities but rather substantial phenomena which fine-tune the biological response. Our review focuses on these functionally relevant interactions between the Ca2+ and the cyclic nucleotide signal transducing pathways hitherto described in the adrenal cortex

Genetic disruption of γ-melanocyte–stimulating hormone signaling leads to salt-sensitive hypertension in the mouse

The γ-melanocyte-stimulating hormone (γ-MSH) is a natriuretic peptide derived from the N-terminal region of proopiomelanocortin (POMC). Evidence suggests that it may be part of the coordinated response to a low-sodium diet (LSD). We tested the effect of the HSD (8% NaCl) compared with LSD (0.07%) on mean arterial pressure (MAP) in mice with targeted disruption of the PC2 gene (PC2(–/–)), necessary for processing of POMC into γ-MSH, or the melanocortin receptor 3 gene (Mc3r(–/–); the receptor for MSH). In wild-type mice, HSD for 1 week did not alter MAP versus LSD mice, but plasma γ-MSH immunoreactivity was more than double the LSD value. In contrast, in PC2(–/–) mice, MAP on the LSD was not greater than in wild-type mice, but plasma γ-MSH was reduced to one-seventh the wild-type value. On the HSD, MAP rose to a markedly hypertensive level while plasma γ-MSH concentration remained severely depressed. Intravenous infusion of γ-MSH (0.2 pmol/min) for 30 min to PC2(–/–) mice after 1 week of HSD lowered MAP from hypertensive levels to normal; infusion of α-MSH at the same rate had no effect. Injection of 60 fmol of γ-MSH into the lateral cerebral ventricle of hypertensive mice also lowered MAP to normal. Administration of a stable analogue of γ-MSH intra-abdominally by microosmotic pump to PC2(–/–) mice prevented the development of hypertension when ingesting the HSD. In mice with targeted disruption of the Mc3r gene, the HSD also led to marked hypertension accompanied by elevated plasma levels of γ-MSH; infusion of exogenous γ-MSH to these mice had no effect on MAP. These results strongly suggest that PC2-dependent processing of POMC into γ-MSH is necessary for the normal response to the HSD. γ-MSH deficiency results in marked salt-sensitive hypertension that is rapidly improved with exogenous γ-MSH through a central site of action. α-MSH infused at the same rate had no effect on MAP, indicating that the hypertension is a specific consequence of impaired POMC processing into γ-MSH. Absence of Mc3r produces γ-MSH resistance and hypertension on the HSD. These findings demonstrate a novel pathway mediating salt-sensitivity of blood pressure