title: Human 5-HT7 receptor-induced inactivation of forskolin-stimulated adenylate cyclase by risperidone, 9-OH-risperidone and other "inactivating antagonists".
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.
authors.affiliation: Center for Neuropharmacology and Neuroscience, Albany Medical College, 47 New Scotland Avenue, Albany, NY 12208, USA.
authors.forename: Nicole
authors.initials: N
authors.lastname: Toohey
authors.forename: Michael T
authors.initials: MT
authors.lastname: Klein
authors.forename: Jessica
authors.initials: J
authors.lastname: Knight
authors.forename: Carol
authors.initials: C
authors.lastname: Smith
authors.forename: Milt
authors.initials: M
authors.lastname: Teitler
mesh_terms: D000067956:Adenylyl Cyclase Inhibitors; D000262:Adenylyl Cyclases / Q000378:metabolism; D002460:Cell Line; D005576:Colforsin / Q000494:pharmacology*; D006801:Humans; D007555:Isoxazoles / Q000494:pharmacology*; D000068882:Paliperidone Palmitate; D011743:Pyrimidines / Q000494:pharmacology*; D011985:Receptors, Serotonin / Q000187:drug effects* / Q000378:metabolism; D018967:Risperidone / Q000494:pharmacology*; D012702:Serotonin Antagonists / Q000494:pharmacology*
chemical_list: D000067956:Adenylyl Cyclase Inhibitors; D007555:Isoxazoles; D011743:Pyrimidines; D011985:Receptors, Serotonin; D012702:Serotonin Antagonists; C104425:serotonin 7 receptor; D005576:Colforsin; D000262:Adenylyl Cyclases; D018967:Risperidone; D000068882:Paliperidone Palmitate