The clinical–molecular interface of somatostatin, dopamine and their receptors in pituitary pathophysiology

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   Figure 1

   (A) Principal intracellular signalling cascades associated to somatostatin receptors in pituitary cells. Somatostatin (or somatostatin analogues) binding to somatostatin receptors inhibits adenylyl cyclase, activates K channels and/or inhibits Ca channels. Phosphotyrosine phosphatases and mitogen-activated protein kinase are modulated as well and along the stimulation of phosphotyrosine phosphatase, may also produce cytostatic actions. More recently, increase in apoptosis via p53 has been shown as well. Most of these effects are mediated by G proteins. (B) Principal signal transduction associated with the activation of dopamine receptors in pituitary cells. Dopamine (or dopamine agonists) binding to pituitary D₂ receptors inhibits adenylyl cyclase, phosphatidylinositol metabolism, activates voltage-activated potassium channels and decreases voltage-activated L-type and T-type calcium currents, modulates the activity of phospholipase C, activates the mitogen-activated protein kinase and extracellular signal-regulated kinase pathway. The expression of POU1F1 transcription factor is inhibited by activation of D₂ receptors, exerting a negative control on PRL gene expression. Most of these effects are mediated by G proteins. AC, adenylyl cyclase; ER, endoplasmic reticulum; ERK, extracellular signal-regulated kinase; GSK3β, glycogen synthase kinase 3β; MAPK, mitogen-activated protein kinase; Gα, Gβ and Gγ, G-protein subunit; PDPK1, 3-phosphoinositide-dependent protein kinase 1; pHi, intracellular pH; PLC, phospholipase C; PKA, protein kinase A; PTPase, phosphotyrosine phosphatase.
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   Figure 2

   Distribution of somatostatin and D₂ dopamine receptors in the different type of pituitary adenomas. The D₂ is the receptor mostly represented in the pituitary tumours and is preferentially associated with sst₂ and sst₅ in somatotroph tumours, with sst₁ and sst₅ in prolactinomas, with sst₃ and sst₂ in clinically non-functioning adenomas and with sst₅ in corticotroph tumours. In mixed and plurihormonal adenomas, a highly heterogeneous pattern is observed.
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   Figure 3

   Somatostatin/dopamine chimera-induced dimerisation of somatostatin and dopamine receptors. Potential intracellular signal transduction pathways linked to the heterodimer. Receptor activation may result in phosphorylation of c-Jun N-terminal kinase that up-regulates P21WAF1/CIP1, while inhibiting transcription of the cyclin, KI67. This combination results in growth arrest of neuroendocrine cells. However, depending on the hybrid receptor complex, P21WAF1/CIP1 transcription can also be decreased (adapted from Kidd et al. 2008). JNK, c-Jun N-terminal kinase.

• © 2009 Society for Endocrinology