Arginine-vasopressin (AVP) plays a determinant role in the normal ACTH response to stress in mammals. We cloned a human cDNA coding a 424 amino acid G-protein coupled receptor structurally related to the vasopressin/oxytocin receptor family . When expressed in COS cells, this receptor binds AVP with a high affinity (Kd = 0.55 f 0.13 nM) and is functionally coupled to phospholipase C. Competition studies with peptidic or non peptidic AVP analogues reveal that it is pharmacologically distinct from Vla and V2 AVP receptors and therefore it is designated V3. RT-PCR analysis shows that the human V3 receptor is expressed in normal pituitary and also in kidney, but is undetectable in liver, myometrium and adrenal gland. Northern blot analysis reveals a -4.8 kb messenger in human corticotropic pituitary adenomas.

Our results show that both vasopressin and CRH receptor genes are overexpressed in ACTH-secreting pituitary tumours. They suggest that overexpression of G protein-coupled receptors may be an additional mechanism through which membrane receptors may play a role in human tumours.

Ectopic ACTH secretion occurs in highly differentiated and rather indolent tumors like bronchial carcinoids or, in contrast, in various types of aggressive and poorly differentiated neuroendocrine tumors. We explored this phenomenon using the recently cloned human pituitary V3 vasopressin receptor as an alternate molecular marker of the corticotroph phenotype. Expression of V3 receptor, corticotrophin releasing hormone (CRH) receptor, and proopiomelanocortin (

In order to assess the mechanisms of proopiomelanocortin (POMC) gene expression in human ACTH-producing tumors, we performed the simultaneous evaluation of POMC products and messenger RNA (mRNA) in tissue fragments obtained from two corticotropic adenomas, five nonpituitary tumors, and two normal human pituitaries. The POMC products were examined using a combination of gel exclusion chromatography and four different radioimmunoassays directed against "3 melanocyte stimulating hormone (y3MSH), ACTH, 'y-lipotropin ('yLPH), and f-endorphin. The POMCmRNA was detected and analyzed by dot and northern blot hybridization using a single-stranded genomic DNA probe corresponding to the coding region of the human POMC gene. Tissue concentrations of POMC products and mRNA showed parallel distributions. Immunoreactive It is concluded that POMC gene expression appears qualitatively unaltered in corticotropic adenomas. In nonpituitary tumors, in contrast, abnormal POMC processing is frequent; in addition, an extra POMCmRNA was detected in a thymic tumor with a greater length than the normal mRNA; the mechanisms and pathophysiological implications of these modifications remain to be elucidated.