Endocrine Abstracts (2004) 7 S14

Somatostatin and dopamine receptors in vitro

Leo J Hofland

Department of Internal Medicine, Section Endocrinology, Erasmus MC, The Netherlands.

The expression of somatostatin (SS) receptors (sst) and dopamine (DA) D2 receptors (D2DR) on pituitary adenomas forms the basis for medical therapy using SS-analogues and DA-agonists. Different types of human pituitary adenomas variably express the five known sst subtypes, as well as D2DR. GH-secreting pituitary adenomas express predominantly sst2 and sst5 mRNA, prolactinomas mainly express sst5 mRNA, while clinically non-functioning pituitary adenomas express sst2 and sst3. In recent years, novel insight has gained in the functional dynamics, as well as crosstalk between G-protein coupled receptors. Sst may undergo homo- or hetero-oligomerization upon ligand activation, and sst5 may form heterodimers with D2DR, resulting in receptor complexes with modified functional properties. These renewed insights in sst and D2DR function initiated the development of several novel compounds binding with high affinity to either individual, or to multiple sst (e.g. universal SS-analogues), including a first generation of chimeric molecules capable of interacting simultaneously with sst and D2DR. The functional activity of these novel compounds has been evaluated in vitro by several research groups. SS-analogues binding with high affinity to sst2 and sst5, suppressed GH- and PRL release by GH-secreting pituitary adenoma cultures significantly more compared with sst2-selective analogues, such as octreotide and lanreotide. The chimeric compound BIM-23A387 that binds to both sst2 and D2DR, has significant enhanced potency of inhibiting GH- and PRL secretion in vitro as well. Finally, sst5 seems the key sst in regulating PRL secretion by human prolactinoma cells in vitro. Taken together, the distinct expression pattern of sst and D2DR in pituitary adenomas may have important consequences for the potentials of novel SS-analogues and chimeric compounds to treat patients with pituitary adenomas, and opens a new area of novel medical treatment options in acromegalic patients partially responsive to the current generation of octapeptide SS-analogues.

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