PT  - JOURNAL ARTICLE
AU  - Chris R. Guthrie
AU  - Aaron T. Murray
AU  - Allyn A. Franklin
AU  - Mark W. Hamblin
TI  - Differential Agonist-Mediated Internalization of the Human 5-Hydroxytryptamine 7 Receptor Isoforms
AID  - 10.1124/jpet.104.081919
DP  - 2005 Jun 01
TA  - Journal of Pharmacology and Experimental Therapeutics
PG  - 1003--1010
VI  - 313
IP  - 3
4099  - http://jpet.aspetjournals.org/content/313/3/1003.short
4100  - http://jpet.aspetjournals.org/content/313/3/1003.full
SO  - J Pharmacol Exp Ther2005 Jun 01; 313
AB  - The human 5-hydroxytryptamine 7 (5-HT7) serotonin receptor is a class A G-protein coupled receptor that has three isoforms, 5-HT7(a), 5-HT7(b), and 5-HT7(d), which are produced by alternative splicing. The 5-HT7 receptors are expressed in discrete areas of the brain and in both vascular and gastrointestinal smooth muscle. Central nervous system 5-HT7 receptors may play a role in mood and sleep disorders. 5-HT7 receptors show high affinity for a number of antidepressants and typical and atypical antipsychotics. We report here that the human 5-HT7(d) isoform expressed in human embryonic kidney (HEK) 293 cells exhibits a pattern of receptor trafficking in response to agonist that differ from 5-HT7(a) or 5-HT7(b) isoforms. We employed a modification of a live cell-labeling technique to demonstrate that surface 5-HT7(d) receptors are constitutively internalized in the absence of agonist. This is in contrast to 5-HT7(a) and 5-HT7(b) isoforms, which do not show this profound agonist-independent internalization. Indeed, the 5-HT7(d) isoform displays this internalization in the presence of a 5-HT7 -specific antagonist. In addition, the human 5-HT7 isoform shows a diminished efficacy in stimulation of cAMP-responsive reporter gene activity in transfected cells compared with 5-HT7(a) or 5-HT7(b) receptors expressed at comparable levels. Thus, the carboxy-terminal tail of 5-HT7(d), which is the longest among known human 5-HT7 isoforms, may contain a motif that interacts with cellular transport mechanisms that is distinct from 5-HT7(a) and 5-HT7(b). The American Society for Pharmacology and Experimental Therapeutics