Family A Gpcrs 521 Monoaminergic Receptors

The serotonin 5HT1C and 5HT2B, a1b-adrenergic and muscarinic ml, m3, and m5 acetylcholine receptors appear to harbor oncogenic potential. These receptors are able to activate signaling pathways associated with proliferation. They can trans form NIH 3T3 cells in an agonist-dependent manner.8-11 Injection of cells derived from transformed foci expressing these receptors into nude mice results in the generation of tumors, indicating that these receptors may function as protoonco-genes when expressed in NIH 3T3 fibroblasts. Their oncogenic potential can be enhanced when mutational alterations are introduced in sites of the receptor, e.g., the C-terminal region of the third intracellular loop, that render the receptor con-stitutively active.10 Activating mutations within the a1b-adrenergic receptors resulted in enhanced ability for tumor generation in nude mice even in the absence of concomitant catecholamine supplementation.

It is less clear whether histaminergic receptors play a role in proliferation and ultimately in oncogenesis. Histamine, a key regulator in a variety of pathophysiological processes, including inflammation, neurotransmission, and gastric acid secretion, has been associated with tumor progression.412 However, both activation of proliferative and antiproliferative signaling by histamine H1 and H2 receptors has been described.1314 These observations are probably highly dependent on the nature of the cancer cell type. Activation of the H1 receptor was shown recently to transactivate the p-catenin pathway, providing a molecular explanation for a possible link of inflammation and cancer.15 Histamine may be able to facilitate the sensitivity of cells to become more prone to cancerous insults by interfering with the p-catenin pathway, elevating the activity of the TCF/LEF-dependent transcription (see Section 5.2.3).

The dopamine D2 receptor is expressed by pituitary lactotrophs and somatotrophs. Dopamine receptor agonists are potent inhibitors of prolactin (PRL) secretion and are effective in treating prolactinomas, tumors of pituitary lactotrophs that produce prolactin.16 First generation dopamine receptor agonists such as bromocriptine have been available since the mid-1970s and are used widely to treat pituitary tumors. Cabergoline, a new long-acting safe, high-affinity selective D2 agonist has been approved to suppress PRL secretion and reduce tumor size.17 Chimeric ligands that incorporate both intrinsic dopaminergic and somatostatiner-gic properties (see Section by selectively binding to D2 and SSTR2 receptors have shown increased potency in suppressing PRL and growth hormone (GH) and are currently in the experimental phases of investigation for treatment of pituitary tumors. Lipid Messenger Receptors

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