Somatostatin and dopamine receptors as targets for medical treatment of Cushing's Syndrome

Somatostatin (SS) and dopamine (DA) receptors are widely expressed in neuroendocrine tumours that cause Cushing's Syndrome (CS). Increasing knowledge of specific subtype expression within these tumours and the ability to target these receptor subtypes with high-affinity compounds, has driven the search for new SS- or DA-based medical therapies for the various forms of CS. In Cushing's disease, corticotroph adenomas mainly express dopamine receptor subtype 2 (D2) and somatostatin receptor subtype 5 (sst5), whereas sst2is expressed at lower levels. Activation of these receptors can inhibit ACTH-release in primary cultured corticotroph adenomas and compounds that target either sst5(pasireotide, or SOM230) or D2(cabergoline) have shown significant efficacy in subsets of patients in recent clinical studies. Combination therapy, either by administration of both types of compounds separately or by treatment with novel somatostatin-dopamine chimeric molecules (e.g. BIM-23A760), appears to be a promising approach in this respect. In selected cases of Ectopic ACTH-producing Syndrome (EAS), the sst2-preferring compound octreotide is able to reduce cortisol levels effectively. A recent study showed that D2receptors are also significantly expressed in the majority of EAS and that cabergoline may decrease cortisol levels in subsets of these patients. In both normal adrenal tissue as well as in adrenal adenomas and carcinomas that cause CS, sst and DA receptor expression has been demonstrated. Although selected cases of adrenal CS may benefit from sst or DA-targeted treatment, its total contribution to the treatment of these patients is likely to be low as surgery is effective in most cases

Cytosolic protein kinase A mediates the growth hormone (GH)-releasing action of GH-releasing factor in purified rat somatotrophs

The growth hormone (GH)-releasing action of GH-releasing factor (GRF) is known to be cAMP-dependent. However, definitive proof for the involvement of the cAMP-dependent enzyme protein kinase A (PKA) is still lacking. In this study, we characterized the PKA system in purified rat somatotrophs and examined its role in mediating GRF-stimulated GH release under static incubation conditions. PKA enzyme activity was detected only in the cytosolic, but not the particulate fraction of rat somatotrophs. This cytosolic PKA activity exhibited the characteristic cAMP dependence (with ED50 of 0.1 μM), ability to phosphorylate kemptide (a synthetic peptide with a PKA phosphorylation site), and susceptibility to inhibition by the bovine heat-stable PKA inhibitor. GRF treatment (1 pM-1 nM) stimulated the cytosolic PKA activity and GH release from rat somatotrophs in a dose-dependent manner. Time-course studies also demonstrated that activation of cAMP synthesis and PKA activity preceded the GH response to GRF. Stimulation of cytosolic PKA activity in rat somatotrophs by the adenylate cyclase activator forskolin (10 nM-1 μM) and membrane permeant cAMP analog db.cAMP (5 μM-0.5 mM) mimicked the GH-releasing effect of GRF. In contrast, Rp.cAMP, a cAMP antagonist for PKA regulatory subunits, blocked both the cytosolic PKA activity as well as GRF-induced GH release. Similar inhibitions were also observed when an inhibitor for PKA catalytic subunits, H89, was used. Somatostatin (SRIF) (1 nM), the physiological GH-release inhibitor, suppressed the GH response to GRF without affecting the basal or GRF-stimulated PKA activity. SRIF at a higher dose (10 nM) abolished the GH-releasing effect of GRF. In this case, SRIF also induced a small but significant inhibition of GRF-stimulated PKA activity. Taken together, the present study provides direct evidence that PKA enzyme activity is localized only in the cytosol of rat somatotrophs and constitutes an essential component of the signal transduction mechanism for GRF-stimulated GH release. This cytosolic PKA system, however, does not appear to be a major target for the GH-release inhibiting action of SRIF.link_to_subscribed_fulltex