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Recent reports indicate that the efficacy of a particular ligand can vary depending on the receptor\u2010mediated response measured (e.g. activating<jats:styled-content style=\"fixed-case\">G<\/jats:styled-content>proteins, other downstream responses, internalization). Previously, we reported that inverse agonists induce both homo\u2010 and heterologous desensitization, similar to agonist stimulation, at the<jats:styled-content style=\"fixed-case\">G<jats:sub>s<\/jats:sub><\/jats:styled-content>\u2010coupled 5\u2010<jats:styled-content style=\"fixed-case\">HT<\/jats:styled-content><jats:sub>7<\/jats:sub>receptor. The primary objective of this study was to determine whether different inverse agonists at the 5\u2010<jats:styled-content style=\"fixed-case\">HT<\/jats:styled-content><jats:sub>7<\/jats:sub>receptor also induce internalization and\/or degradation of 5\u2010<jats:styled-content style=\"fixed-case\">HT<\/jats:styled-content><jats:sub>7<\/jats:sub>receptors.<\/jats:p><\/jats:sec><jats:sec><jats:title>Experimental Approach<\/jats:title><jats:p><jats:styled-content style=\"fixed-case\">HEK<\/jats:styled-content>293 cells expressing 5\u2010<jats:styled-content style=\"fixed-case\">HT<\/jats:styled-content><jats:sub>7(a, b or d)<\/jats:sub>receptors were pre\u2010incubated with 5\u2010<jats:styled-content style=\"fixed-case\">HT<\/jats:styled-content>, clozapine, olanzapine, mesulergine or<jats:styled-content style=\"fixed-case\">SB<\/jats:styled-content>269970 and their effects upon receptor density, AC activity, internalization, recruitment of \u03b2\u2010arrestins and lysosomal trafficking were measured.<\/jats:p><\/jats:sec><jats:sec><jats:title>Key Results<\/jats:title><jats:p>The agonist 5\u2010<jats:styled-content style=\"fixed-case\">HT<\/jats:styled-content>and three out of four inverse agonists tested increased internalization independently of \u03b2\u2010arrestin recruitment. Among these, only the atypical antipsychotics clozapine and olanzapine promoted lysosomal sorting and reduced 5\u2010<jats:styled-content style=\"fixed-case\">HT<\/jats:styled-content><jats:sub>7<\/jats:sub>receptor density (\u223c60% reduction within 24\u2009h). Inhibition of lysosomal degradation with chloroquine blocked the clozapine\u2010 and olanzapine\u2010induced down\u2010regulation of 5\u2010<jats:styled-content style=\"fixed-case\">HT<\/jats:styled-content><jats:sub>7<\/jats:sub>receptors. Incubation with<jats:styled-content style=\"fixed-case\">SB<\/jats:styled-content>269970 decreased both 5\u2010<jats:styled-content style=\"fixed-case\">HT<\/jats:styled-content><jats:sub>7(b)<\/jats:sub>constitutive internalization and receptor density but increased 5\u2010<jats:styled-content style=\"fixed-case\">HT<\/jats:styled-content><jats:sub>7(d)<\/jats:sub>receptor density, indicating differential ligand regulation among the 5\u2010<jats:styled-content style=\"fixed-case\">HT<\/jats:styled-content><jats:sub>7<\/jats:sub>splice variants.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions and Implications<\/jats:title><jats:p>Taken together, we found that various ligands differentially activate regulatory processes governing receptor internalization and degradation in addition to signal transduction. Thus, these data extend our understanding of functional selectivity at the 5\u2010<jats:styled-content style=\"fixed-case\">HT<\/jats:styled-content><jats:sub>7<\/jats:sub>receptor.<\/jats:p><\/jats:sec>","DOI":"10.1111\/bph.13169","type":"journal-article","created":{"date-parts":[[2015,4,17]],"date-time":"2015-04-17T10:19:15Z","timestamp":1429265955000},"page":"3846-3860","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":32,"title":["The atypical antipsychotics clozapine and olanzapine promote down\u2010regulation and display functional selectivity at human 5\u2010<scp>HT<\/scp><sub>7<\/sub>receptors"],"prefix":"10.1111","volume":"172","author":[{"given":"K W","family":"Andressen","sequence":"first","affiliation":[{"name":"Department of Pharmacology Institute of Clinical Medicine University of Oslo and Oslo University Hospital Oslo Norway"},{"name":"K.G. 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