ECE2009 Symposia Pituitary cell biology (4 abstracts)
Somatostatin acts as an inhibitor of hormonal secretion and cell proliferation by acting through 5 somatostatin receptors subtypes (sst15). Coupling with Gi/o proteins is associated with effects on various transduction pathways, as adenylate cyclase inhibition or phosphatases activation. Dopamine receptor subtype 2 (D2DR) acts through coupling with similar G-proteins and transduction pathways. Sst, mostly sst2 and sst5, are coexpressed with D2DR in many neuroendocrine normal or tumoral cells. Both sst2 and sst5 are able to form heterodimers with D2DR, modifying ligands binding and signal transduction in a positive cooperation manner. Coactivation (of sst2 and D2DR) with clinically available sst2 (octreotide, lanreotide) and D2DR agonists (cabergoline) in different tumors or cellular models is rarely associated with additive effects in the suppression of cell secretion and proliferation. Availability of hybrid dopamine and somatostatin agonists (dopastatins), combining in the same molecule structural parts of somatostatin and dopamine, opened new possibilities for sst-D2DR cooperation. In the first and most studied cellular model, GH tumoral cells in vitro, dopastatins showed clearly a synergic effect on cell secretion and proliferation by acting through both sst and D2DR receptors. In others pituitary tumors as lactotroph and gonadotroph and in most other neuroendocrine and non-neuroendocrine cellular models, coexpressing various levels of sst and D2DR, dopastatins showed an effect closer to that of D2DR agonists. Transduction pathways involved in sst D2DR cooperation is currently under investigation in various cell models, while a dopastatins, BIM-23A760, is starting clinical studies in acromegaly.