Human 5-HT7 receptor-induced inactivation of forskolin-stimulated adenylate cyclase by risperidone, 9-OH-risperidone and other "inactivating antagonists".
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Toohey N, Klein MT, Knight J, Smith C, Teitler M
Human 5-HT7 receptor-induced inactivation of forskolin-stimulated adenylate cyclase by risperidone, 9-OH-risperidone and other "inactivating antagonists".
Mol Pharmacol. 2009 Sep;76(3):552-9. doi: 10.1124/mol.109.056283. Epub 2009 Jun 9.
- PubMed ID
- 19509219 [ View in PubMed]
- Abstract
We have previously reported on the unusual human 5-hydroxytryptamine(7) (h5-HT(7)) receptor-inactivating properties of risperidone, 9-OH-risperidone, bromocriptine, methiothepin, metergoline, and lisuride. Inactivation was defined as the inability of 10 microM 5-HT to stimulate cAMP accumulation after brief exposure and thorough removal of the drugs from HEK293 cells expressing h5-HT(7) receptors. Herein we report that brief exposure of the h5-HT(7) receptor-expressing cells to inactivating drugs, followed by removal of the drugs, results in potent and efficacious irreversible inhibition of forskolin-stimulated adenylate cyclase activity. Pretreatment, followed by removal of the inactivating drugs inhibited 10 microM forskolin-stimulated adenylate cyclase activity with potencies similar to the drugs' affinities for the h5-HT(7) receptor. The actions of the inactivating drugs were pertussis toxin-insensitive, indicating the lack of G(i) in their mechanism(s) of action. Methiothepin and bromocriptine maximally inhibited 10 microM forskolin-stimulated adenylate cyclase, whereas the other drugs produced partial inhibition, indicating the drugs are inducing slightly different inactive conformations of the h5-HT(7) receptor. Maximal effects of these inactivating drugs occurred within 15 to 30 min of exposure of the cells to the drugs. A G(s)-mediated inhibition of forskolin-stimulated activity has never been reported. The inactivating antagonists seem to induce a stable conformation of the h5-HT(7) receptor, which induces an altered state of G(s), which, in turn, inhibits forskolin-mediated stimulation of adenylate cyclase. These and previous observations indicate that the inactivating antagonists represent a unique class of drugs and may reveal GPCR regulatory mechanisms previously unknown. These drugs may produce innovative approaches to the development of therapeutic drugs.
DrugBank Data that Cites this Article
- Drug Targets
Drug Target Kind Organism Pharmacological Action Actions Lisuride 5-hydroxytryptamine receptor 7 Protein Humans UnknownNot Available Details Paliperidone 5-hydroxytryptamine receptor 7 Protein Humans UnknownNot Available Details