Rationale: The h5-HT(7) receptor is subject to inactivation by risperidone and 9-OH-risperidone, apparently through a pseudo-irreversible complex formed between these drugs and the receptor. Although risperidone and 9-OH-risperidone ("inactivating antagonists") completely inactivate the receptor, only 50% of the receptors form a pseudo-irreversible complex with these drugs.
Objectives: This study aims to more fully determine the mechanism(s) responsible for the novel effects of risperidone and 9-OH-risperidone and to determine if the inactivation can be reversed (reactivation).
Methods: The ability of non-inactivating drugs (competitive antagonists) to dissociate wash-resistant [(3)H]risperidone binding from h5-HT(7) receptors was investigated. Also, the ability of non-inactivating drugs to reactivate inactivated h5-HT(7) receptors was investigated, using cAMP accumulation as a functional endpoint.
Results: The competitive (non-inactivating) antagonists clozapine and mesulergine released the wash-resistant [(3)H]risperidone binding to the h5-HT(7) receptor. The competitive antagonists clozapine, SB269970, mianserin, cyproheptadine, mesulergine, and ICI169369 reactivated the risperidone-inactivated h5-HT(7) receptors in a concentration-dependent manner. The potencies for reactivation closely match the affinities of these drugs for the h5-HT(7) receptor (r(2) = 0.95), indicating that the reactivating antagonists are binding to and producing their effects through the orthosteric binding site of the h5-HT(7) receptor. Bioluminescence resonance energy transfer analyses indicate that the h5-HT(7) receptor forms homodimers.
Conclusions: The ability of the non-inactivating drugs to bind h5-HT(7) orthosteric sites and reverse the wash-resistant effects of risperidone or 9-OH-risperidone, also bound to h5-HT(7) orthosteric sites, is evidence for protomer-protomer interactions between h5-HT(7) homodimers. This is the first demonstration of a non-mutated G-protein-coupled receptor homodimer engaging in protomer-protomer interactions in an intact cell preparation.
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| http://dx.doi.org/10.1007/s00213-010-2001-x | DOI Listing |
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