title: Differential agonist-mediated internalization of the human 5-hydroxytryptamine 7 receptor isoforms.
abstract: The human 5-hydroxytryptamine 7 (5-HT(7)) serotonin receptor is a class A G-protein coupled receptor that has three isoforms, 5-HT(7(a)), 5-HT(7(b)), and 5-HT(7(d)), which are produced by alternative splicing. The 5-HT(7) receptors are expressed in discrete areas of the brain and in both vascular and gastrointestinal smooth muscle. Central nervous system 5-HT(7) receptors may play a role in mood and sleep disorders. 5-HT(7) receptors show high affinity for a number of antidepressants and typical and atypical antipsychotics. We report here that the human 5-HT(7(d)) isoform expressed in human embryonic kidney (HEK) 293 cells exhibits a pattern of receptor trafficking in response to agonist that differ from 5-HT(7(a)) or 5-HT(7(b)) isoforms. We employed a modification of a live cell-labeling technique to demonstrate that surface 5-HT(7(d)) receptors are constitutively internalized in the absence of agonist. This is in contrast to 5-HT(7(a)) and 5-HT(7(b)) isoforms, which do not show this profound agonist-independent internalization. Indeed, the 5-HT(7(d)) isoform displays this internalization in the presence of a 5-HT(7) -specific antagonist. In addition, the human 5-HT(7) isoform shows a diminished efficacy in stimulation of cAMP-responsive reporter gene activity in transfected cells compared with 5-HT(7(a)) or 5-HT(7(b)) receptors expressed at comparable levels. Thus, the carboxy-terminal tail of 5-HT(7(d)), which is the longest among known human 5-HT(7) isoforms, may contain a motif that interacts with cellular transport mechanisms that is distinct from 5-HT(7(a)) and 5-HT(7(b)).
authors.affiliation: Veterans Affairs Puget Sound Health Care System, Seattle, WA 98108, USA. cguthrie@u.washington.edu
authors.forename: Chris R
authors.initials: CR
authors.lastname: Guthrie
authors.forename: Aaron T
authors.initials: AT
authors.lastname: Murray
authors.forename: Allyn A
authors.initials: AA
authors.lastname: Franklin
authors.forename: Mark W
authors.initials: MW
authors.lastname: Hamblin
mesh_terms: D001692:Biological Transport; D002460:Cell Line; D000242:Cyclic AMP / Q000502:physiology; D006801:Humans; D020033:Protein Isoforms; D011985:Receptors, Serotonin / Q000032:analysis / Q000378:metabolism*; D017366:Serotonin Receptor Agonists / Q000494:pharmacology*
chemical_list: D020033:Protein Isoforms; D011985:Receptors, Serotonin; D017366:Serotonin Receptor Agonists; C104425:serotonin 7 receptor; D000242:Cyclic AMP