A Two-Step Mechanism by Which Corticotropin- Releasing Hormone Releases Hypothalamic β-Endorphin: The Role of Vasopressin and G-Proteins*
- 1 September 1989
- journal article
- research article
- Published by The Endocrine Society in Endocrinology
- Vol. 125 (3) , 1365-1372
- https://doi.org/10.1210/endo-125-3-1365
Abstract
It is well established that in the pituitary gland corticotropin-releasing hormone (CRH) stimulates the release of .beta.-endorphin (.beta.-E) via a cAMP-linked mechanism. Studies of the mechanisms underlying the CRH stimulation of .beta.-E release from rat hypothalamic slices perifused in vitro are reported in this paper. The data indicate that both a cAMP-dependent and non-cAMP-dependent mechanism mediate the action of CRH in the hypothalamus. The presence of a cAMP-linked mechanism was suggested by the finding that cholera toxin (0.1-10 nM) and forskolin (2.5 .times. 10-6 M), both of which act to raise intracellular cAMP levels, stimulated the release of .beta.-E. In both cases, no further stimulation was seen upon addition of CRH (10-8 M). However, it was also found that preincubation of the tissue with pertussis toxin (PTX; 100 ng/ml) prevented both the CRH- and forskolin-stimulated release of .beta.-E. This indicated that, in addition to the cAMP-linked mechanism, a further messenger system which is connected to a PTX-sensitive G-protein may also play a role. The latter observation also implied that a further substance, which utilizes a separate second messenger system, might be involved in the CRH stimulation of .beta.-E release. In this regard the role of arginine vasopressin (AVP) was investigated due to the known interaction between CRH and AVP in the pituitary gland. AVP (10-12 to 10-6 M) itself potently and dose-dependently stimulated .beta.-E release, producing a maximal increase of 220% above basal levels. The AVP-induced release of .beta.-E was abolished in PTX-pretreated hypothalami. The apparently obligatory requirement of AVP for the CRH-stimulation of .beta.-E release was illustrated by the finding that blockade of AVP receptors using the AVP antagonist d(CH2)5 [Tyr(OEt)2,Val4]-AVP almost completely attenuated the CRH-stimulated release of .beta.-E. Furthermore, in the presence of a high concentration of AVP (10-6 M) no further stimulation of release was seen with CRH (10-8 M). These data therefore strongly indicate that CRH acts via the intermediacy of AVP to release .beta.-E from hypothalamic slices in vitro and that two separate second messenger systems are involved: a cAMP-linked mechanism connected to a cholera toxin-sensitive G-protein (CRH) and a second system linked to a PTX-sensitive G-protein (AVP).Keywords
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