Rat TRH receptor type 2 exhibits higher basal signaling activity than TRH receptor type 1

Two types of rat TRH receptor (TRH-R1 and TRH-R2) have been identified and shown previously to exhibit similar binding and stimulated signaling activi ty via the phosphoinositide-calcium transduction pathway. Since mouse TRH-R 1 exhibits basal (or constitutive or ligand-independent) signaling activity , we compared basal signaling by TRH-R1 and TRH-R2. Basal signaling was mea sured as receptor-mediated reporter gene induction via different transcript ion factors. We found that TRH-R2 exhibited higher basal signaling activity than TRH-R1 via pathways mediated by transcription factors AP-1, Elk-1 and CREB. Furthermore, CREB-mediated transcription was directly dependent on t he level of TRH-R2 expression and was inhibited by midazolam, a specific in verse agonist of basal TRH-R signaling. Since TRH-R1 and TRH-R2 exhibit dis tinct anatomic distributions in the rat, it is possible that TRH ligand-ind ependent signaling is more important in tissues/cells in which TRH-R2 is ex pressed and less important in tissues in which TRH-R1 is found.