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Differences in the C‐terminus contribute to variations in trafficking between rat and human 5‐HT 2A receptor isoforms: identification of a primate‐specific tripeptide ASK motif that confers GRK‐2 and β arrestin‐2 interactions
Author(s) -
Bhattacharya Aditi,
Sankar Shobhana,
Panicker Mitradas M.
Publication year - 2010
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1111/j.1471-4159.2009.06493.x
Subject(s) - internalization , gene isoform , receptor , biology , hek 293 cells , 5 ht7 receptor , microbiology and biotechnology , enzyme linked receptor , g protein coupled receptor , 5 ht5a receptor , 5 ht receptor , biochemistry , serotonin , gene
J. Neurochem. (2010) 112 , 723–732. Abstract Internalization and recycling of G‐protein coupled receptors are important cellular processes regulating receptor function. These are receptor‐subtype and cell type‐specific. Although important, trafficking variations between receptor isoforms of different species has received limited attention. We report here, differences in internalization and recycling between rat and human serotonin 2A receptor (5‐HT 2A R) isoforms expressed in human embryonic kidney 293 cells in response to serotonin. Although the human and rat 5‐HT 2A Rs differ by only a few amino acids, the human receptor takes longer to recycle to the cell surface after internalization, with the additional involvement of β arrestin‐2 and G‐protein receptor kinase 2. The interaction of β arrestin‐2 with the human receptor causes the delay in recycling and is dependent on a primate‐specific ASK motif present in the C‐terminus of the receptor. Conversion of this motif to NCT, the corresponding sequence present in the rat isoform, results in the human isoform trafficking like the rat receptor. Replacing the serine 457 with alanine in the ASK motif of human isoform resulted in faster recycling, although with continued arrestin‐dependent internalization. This study establishes significant differences between the two isoforms with important implications in our understanding of the human 5‐HT 2A R functions; and indicates that extrapolating results from non‐human receptor isoforms to human subtypes is not without caveats.