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Persistent signaling by thyrotropin‐releasing hormone receptors correlates with G‐protein and receptor levels
Author(s) -
Boutin Alisa,
Allen Michael D.,
Neumann Susanne,
Gershengorn Marvin C.
Publication year - 2012
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fj.12-207860
Subject(s) - internalization , receptor , thyrotropin releasing hormone , endocrinology , medicine , agonist , signal transduction , g protein coupled receptor , chemistry , hormone , g protein , thyrotropin releasing hormone receptor , biology , hormone receptor , microbiology and biotechnology , cancer , breast cancer
G‐protein‐coupled receptors with dissociable agonists for thyrotropin, parathyroid hormone, and sphingosine‐1‐phosphate were found to signal persistently hours after agonist withdrawal. Here we show that mouse thyrotropin‐releasing hormone (TRH) receptors, subtypes 2 and 1(TRH‐R2 and TRH‐R1), can signal persistently in HEK‐EM293 cells under appropriate conditions, but TRH‐R2 exhibits higher persistent signaling activity. Both receptors couple primarily to Gα q/11 . To gain insight into the mechanism of persistent signaling, we compared proximal steps of inositolmonophosphate (IP1) signaling by TRH‐Rs. Persistent signaling was not caused by slower dissociation of TRH from TRH‐R2 ( t 1/2 =77±8.1 min) compared with TRH‐R1 ( t 1/2 =82±12 min) and was independent of internalization, as inhibition of internalization did not affect persistent signaling (115% of control), but required continuously activated receptors, as an inverse agonist decreased persistent signaling by 60%. Gα q/11 knockdown decreased persistent signaling by TRH‐R2 by 82%, and overexpression of Gα q/11 induced persistent signaling in cells expressing TRH‐R1. Lastly, persistent signaling was induced in cells expressing high levels of TRH‐R1. We suggest that persistent signaling by TRHRs is exhibited when sufficient levels of agonist/receptor/G‐protein complexes are established and maintained and that TRH‐R2 forms and maintains these complexes more efficiently than TRH‐R1.—Boutin, A., Allen, M. D., Neumann, S., Gershengorn, M. C. Persistent signaling by thyrotropin‐releasing hormone receptors correlates with G‐protein and receptor levels. FASEB J. 26, 3473–3482 (2012). www.fasebj.org