Adrenocorticotrophic hormone

Adrenocorticotrophic hormone (ACTH), a product of the Pro-opiomelanocortin (POMC) gene, is a hormone secreted by the corticotrophs of the anterior pituitary in response to hypothalamic releasing-factors (Corticotrophin releasing factor, CRF).

All of the hormones of the anterior pituitary gland (the adenohypophysis) are released from endocrine cells that, in mammals, are not directly innervated, yet the release of these hormones remains under the control of the brain. The brain exerts its control over the anterior pituitary gland by means of releasing factors and release-inhibiting factors; these are blood-borne substances that are released by hypothalamic neurones into a system of blood vessels at the base of the brain - at the median eminence. These vessels, the hypothalamo-hypophysial portal vessels, transport the hypothalamic factors to the adenohypophysis where they bind to specific receptors on the surface of the hormone-producing cells.

Early studies showed that when the pituitary is disconnected from the hypothalamus, ACTH output falls. Attempts to localise the hypothalamic source of a releasing factor for ACTH focussed attention upon the paraventricular nucleus, and gave rise to the theory that the peptide vasopressin might be the releasing factor. When given in large amounts, vasopressin will result in ACTH release; the pituitary corticotrophs express a vasopressin receptor subtype (V1b) which differs pharmacologically from both the vascular (V1a) receptors and the renal (V2) receptors; However the hypothesis that vasopressin was the releasing factor for ACTH fell from favour when it became clear that:

1) plasma concentrations of ACTH and vasopressin show no consistent correlation; and

2) the Brattleboro rat hypothalamus has high CRF activity but no vasopressin (The Brattleboro rat is a genetic mutant with hereditary diabetes insipidus resulting from a total inability to synthesize vasopressin)

A 41 amino acid CRF peptide was subsequently isolated and sequenced. This peptide is quite distinct from vasopressin, but is also localised to the paraventricular nucleus. Whereas vasopressin is mainly present in magnocellular neurones which project to the posterior pituitary, CRF is present in parvocellular neurones which project to the external layer of the median eminence, where it is secreted into the portal blood. The CRF neurones contain receptors for glucocorticoids, which exert an inhibitory, negative-feedback control on CRF release.

However, while CRF is a potent secretagogue for ACTH, its actions are strongly potentiated in the presence of vasopressin, a finding which gave rise to the suggestion that vasopressin and CRF are co-regulators of ACTH secretion.

Following adrenalectomy, which removes the negative feedback effects of circulating glucocorticoids, the amount of vasopressin in the external layer of the median eminence increases markedly, and this increase can be prevented by replacement of glucocorticoids but not mineralocorticoids; the expression of vasopressin in magnocellular neurones however appeared to be unaffected by adrenalectomy, suggesting that the increased vasopressin in the median eminence must derive from different vasopressin cells.

After adrenalectomy, the CRF cells increase their synthesis of CRF, and the CRF-containing terminals in the median eminence increase in number and staining density. Moreover, and Importantly, after adrenalectomy about 79% of the CRF neurones in the paraventricular nucleus also begin to express both vasopressin and its mRNA, suggesting that populations of hypothalamic neurones can "switch on" the synthesis of more than one active substance in response to physiological challenges.

Thus ACTH secretion is regulated by a subpopulation of the parvocellular neurones in the paraventricular nucleus. This subpopulation consists of neuroendocrine neurosecretory neurones that project to the median eminence; they normally synthesize CRF but can additionally synthesize vasopressin, especially in response to physiological challenge. Vasopressin and CRF are both secretagogues for ACTH, and in combination they have synergistic actions on ACTH release.

References

• Ma X-M, Lightman SL The arginine vasopressin and corticotrophin-releasing hormone gene transcription responses to varied frequencies of repeated stress in rats J Physiol 510: 605-

• Ferrini MG et al. (1997) Sex difference in glucocorticoid regulation of vasopressin mRNA in the paraventricular hypothalamic nucleus” Cell Mol Neurobiol 17: 671-86

• Kovacs KJ et al. (1998) Protein synthesis blockade differentially affects the stress-induced transcriptional activation of neuropeptide genes in parvocellular neurosecretory neurons Mol Brain Res 54:85-91

• Pelton GH et al. (1997) Repeated stress, like vasopressin, sensitizes the excitatory effects of corticotropin releasing factor on the acoustic startle reflex Brain Res 19;778:381-7