Pancreatic vasopressin V1breceptors: characterization in In-R1-G9 cells and localization in human pancreas

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Abstract
Vasopressin (AVP) receptors present in In-R1-G9 cells, a hamster glucagon-secreting α-pancreatic cell line, were characterized using SSR-149415, a selective nonpeptide V1breceptor antagonist, and reference AVP compounds. Binding experiments, using [3H]AVP as a ligand, identified a single population of high-affinity binding sites. SSR-149415 competitively inhibited this binding and exhibited nanomolar and stereospecific affinity for these sites. The affinity of various AVP/oxytocin ligands confirmed a V1bbinding profile. In functional studies, AVP was a potent stimulant in inducing intracellular Ca2+increase, glucagon secretion, and cell proliferation. These effects were fully antagonized by SSR-149415 with a nanomolar potency, whereas its diasteroisomer as well as two selective V1aand V2receptor antagonists were much less potent. Additionally, the order of potency of AVP agonists and antagonists was in agreement with V1b-mediated effects. By RT-PCR, we confirmed the presence of V1breceptor mRNA in both In-R1-G9 cells and in human pancreas. The distribution pattern of V1breceptors investigated in human pancreas by immunohistochemistry showed strong labeling in islets of Langerhans, and colocalization studies indicated that this receptor was expressed in α-glucagon, β-insulin, and somatostatin pancreatic cells. Thus, in In-R1-G9 cells, AVP mediates intracellular Ca2+increase, glucagon secretion, and cell proliferation by activating V1breceptors, and these effects are potently antagonized by SSR-149415. Moreover, the presence of V1breceptors also found in human Langerhans islets could suggest hormonal control of AVP in human pancreas.