Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.1.4.3 (phospholipase C)
 18,461 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Vasopressin (VP) stimulates pituitary ACTH secretion through interaction with receptors of the V1b subtype (V1bR, V3R), located in the plasma membrane of the pituitary corticotroph, mainly by potentiating the stimulatory effects of corticotropin releasing hormone (CRH). Chronic stress paradigms associated with corticotroph hyperresponsiveness lead to preferential expression of hypothalamic VP over CRH and upregulation of pituitary V1bR, suggesting an important role for VP during adaptation of the hypothalamic-pituitary-adrenal (HPA) axis to stress. Vasopressinergic regulation of ACTH secretion depends on the number of V1bRs as well as coupling of the receptor to phospholipase C (PLC) in the pituitary. Regulation of V1bR gene transcription may involve a number of regulatory elements in the promoter region, of which a GAGA box was shown to be essential. Although V1bR gene transcription is necessary to maintain V1bR mRNA levels, the lack of correlation between VP binding and V1bR mRNA suggests that regulation of mRNA translation is a major regulatory step of the number of V1bRs. V1bR translation appears to be under tonic inhibition by upstream minicistrons and positive regulation through protein kinase C (PKC) activation of an internal ribosome entry site (IRES) in the 5' untranslated region (5'UTR) of the mRNA. The data provide mechanisms by which regulation of hypothalamic VP and pituitary V1bR content contribute to controlling HPA axis activity during chronic stress.
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PMID:Vasopressinergic regulation of the hypothalamic pituitary adrenal axis and stress adaptation. 1551 50

Malignant growth of small-cell lung carcinoma is promoted by various neuroendocrine autocrine/paracrine loops. Therefore, to interfere with this mitogenic process, it is crucial to elucidate the mechanisms involved. It is known that the oxytocin (OT) and vasopressin (VP) genes, normally transcriptionally restricted in their expression, are activated in small-cell lung cancer (SCLC), concomitantly with expression of their receptors (OTR, V1aR, V1bR/V3R and V2R). The aim of the present study was to characterize, in concentrations close to physiological and pharmacological conditions, intracellular signalling events triggered by OT and VP binding to their specific receptors in SCLC cells and to identify factors mediating OT- and VP-induced mitogenic effects on SCLC. Known agonists for OTR ([Thr4,Gly7]OT) and V1aR (F180), in addition to OT and VP, were able to elicit increases in cytosolic Ca2+ levels and this effect could be blocked using an OTR antagonist (OVTA) or a V1aR antagonist (SR49059) respectively. There was no activation of the cAMP pathway detected after VP, dDAVP (a V2R agonist), or OT treatment. Stimulation of SCLC cells with OT and VP led to an increase of extracellular signal-regulated kinase (ERK) 1/2 phosphorylation, maximal at 5 min, and the subsequent phosphorylation of its downstream target p90 ribosomal S6 kinase (p90RSK). Pre-incubation with OVTA and SR49059, and with inhibitors of phospholipase C (PLC), protein kinase C (PKC), mitogen-activated protein kinase/ERK kinase (MEK) 1/2 and a Ca2+ chelator significantly reduced OT- and VP-induced ERK1/2 phosphorylations. OVTA, SR49059 as well as MEK1/2 and PKC inhibitors also downregulated OT- and VP-induced p90RSK phosphorylation. In [3H]thymidine-uptake experiments, we subsequently observed that PLC, Ca2+, PKC and ERK1/2 are absolutely required for the OT- and VP-stimulated SCLC cellular growth process. In conclusion, the results presented here indicate that OT- and VP-induced mitogenic effects on SCLC are respectively mediated by OTR and V1aR signalling and that this mitogenic signalling passes through the phosphorylation of ERK1/2 and p90RSK in a PLC-, Ca2+-, PKC- and MEK1/2-dependent pathway.
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PMID:Oxytocin- and vasopressin-induced growth of human small-cell lung cancer is mediated by the mitogen-activated protein kinase pathway. 1561 60

Vasopressin, a hypothalamic hormone, acts on its target tissues via three different G protein coupled receptors. The vasopressin V1a and V1b receptors, associated to Gq protein and phospholipase C, are responsible for vasoconstriction and regulation of the corticotroph axis respectively. The V2 vasopressin receptor is coupled to Gs protein and adenylyl cyclase and is responsible for water reabsorption in the renal collecting duct. Mutations of the V2 receptor are involved in diabetes insipidus and most of these mutations result in an endoplasmic reticulum (ER) retention of the mutated receptor. With the V1b receptor model, we have identified a proximal sequence of the C-terminal segment, which is crucial for ER export. Mutations in this short domain result in ER accumulation and degradation of the receptor. SSR 149415, a nonpeptide antagonist of V1bR, which is permeable to cell membrane, is able to rescue the mutant phenotype and acts as a pharmacological chaperone.
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PMID:[Vasopressin receptors: structure/function relationships and signal transduction in target cells]. 1673 30