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CELLULAR AND MOLECULAR

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

Veteran's Affairs Puget Sound Health Care System, Seattle, Washington (C.R.G., A.T.M., A.A.F., M.W.H.); and Department of Psychiatry and Behavioral Sciences, University of Washington, Seattle, Washington (M.W.H.)

The human 5-hydroxytryptamine 7 (5-HT₇) 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-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-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-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-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-HT₇ isoforms, may contain a motif that interacts with cellular transport mechanisms that is distinct from 5-HT_7(a) and 5-HT_7(b).

Address correspondence to: Chris R. Guthrie, Veterans Affairs Puget Sound Health Care System, 1660 S. Columbian Way, Seattle, WA 98108. E-mail: cguthrie{at}u.washington.edu

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