Differential Agonist-Mediated Internalization of the Human 5-Hydroxytryptamine 7 Receptor Isoforms

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...

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Bibliographic Details
Published in:The Journal of pharmacology and experimental therapeutics 2005-06, Vol.313 (3), p.1003-1010
Main Authors: Guthrie, Chris R, Murray, Aaron T, Franklin, Allyn A, Hamblin, Mark W
Format: Article
Language:English
Subjects:
Biological Transport
Cell Line
Cyclic AMP - physiology
Humans
Protein Isoforms
Receptors, Serotonin - analysis
Receptors, Serotonin - metabolism
Serotonin Receptor Agonists - pharmacology
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Summary: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) .
ISSN:0022-3565
1521-0103
DOI:10.1124/jpet.104.081919