Acute and Chronic Regulation of Pituitary Receptors for Vasopressin and Corticotropin Releasing Hormone

Abstract

At least two hypothalamic peptides, corticotropin releasing hormone (CRH) and vasopressin (VP), are important in regulating adrenocorticotropin (ACTH) release from the anterior pituitary. Both are secreted in a pulsatile manner and stimulate ACTH secretion by interacting with G protein-coupled receptors (GPCRs), namely the type 1 CRH receptor and V1b receptor, respectively. Repeated or prolonged stimulation with either peptide can cause reduced ACTH responsiveness or desensitisation, both in vivo and in vitro. Desensitisation of perifused sheep anterior pituitary cells to VP was found to be rapid and occurred following treatment with 5 nM VP for 5 min. This is within the range of concentrations and durations of VP pulses seen in sheep portal blood during acute stress. In contrast, significant desensitisation of the ACTH response to CRH required pre-treatment for longer than 25 min with a CRH concentration of 1 nM, suggesting that endogenous pulses may not elicit desensitisation. Although rapid GPCR desensitisation involves uncoupling of receptors from their G proteins, commonly mediated by receptor phosphorylation, and internalisation of receptors, desensitisation of neither the CRH nor VP receptor was mediated by PKA or PKC, respectively. Desensitisation of the response to VP was found to be dependent upon receptor internalisation, and resensitisation could be delayed by treatment with a protein phosphatase 2B inhibitor. The rapid kinetics of desensitisation of the ACTH response to VP suggest that this process is important in regulating the response to acute rather than chronic stress. If, as has been suggested, CRH acts in a permissive way to set corticotrope gain, desensitisation to CRH could also be important in long term regulation of ACTH secretion.

Stress-Induced Sensitization of the Hypothalamic-Pituitary Adrenal Axis Is Associated with Alterations of Hypothalamic and Pituitary Gene Expression

“…Repeated or prolonged stimulation with CRH reduces CRH receptor binding and can cause reduced ACTH responsiveness or desensitization [31]. Indeed chronically activated corticotrophs generally show blunted ACTH response to CRH [32].…”

Regulation of the expression and secretion of urocortin 2 in rat pituitary

“…We also found that CRF stimulates the expression level of POMC mRNA and secretion of ACTH in anterior lobe cells, while vasopressin stimulates the secretion of ACTH but not the expression of POMC mRNA in accordance with previous reports (Giguere & Labrie 1982, Aguilera et al 1983. The adenylate cyclaseprotein kinase A (PKA) pathway mediates CRF-induced secretion of POMC-derived peptides, while AVP increases the secretion of POMC-derived peptides via the phospholipase C (PLC)-protein kinase C (PKC) pathway (Mason et al 2002), indicating the intracellular signaling cascade under CRF is different from that under vasopressin. It therefore seems that the secretion of Ucn 2 is dependent on the adenylate cyclase-PKA pathway, while that of POMCderived peptides is dependent on either the adenylate cyclase-PKA or PLC-PKC pathways.…”

Vasoactive intestinal peptide impairs leucocyte migration but fails to modify experimental murine colitis

“…Given that a number of G protein-coupled hormone receptors respond physiologically to pulsatile administration of ligand rather than to steady state levels [30], we examined the effects of VIP (1 and 5 nmol) given intermittently by i.p. injection over 7 days.…”

“…Several G protein-coupled receptors respond physiologically to pulsatile administration of their cognate ligands, rather than to steady-state levels [30]. In addition, a recent study by Abad et al reported the therapeutic and prophylactic effects of VIP delivered intraperitoneally in mice with TNBS colitis [27].…”