Cyclic Adenosine 3,5-Monophosphate (cAMP)-Dependent Protein Kinases, But Not Exchange Proteins Directly Activated by cAMP (Epac), Mediate Thyrotropin/cAMP- Dependent Regulation of Thyroid Cells

TSH, mainly acting through cAMP, is the principal physiological regulator of thyroid gland function, differentiation expression, and cell proliferation. Both cAMP-dependent protein kinases [protein kinase A (PKA)] and the guanine-nucleotide-exchange factors for Rap proteins, exchange proteins directly activated by cAMP (Epac) 1 and Epac2, are known to mediate a broad range of effects of cAMP in various cell systems. In the present study, we found a high expression of Epac1 in dog thyrocytes, which was further increased in response to TSH stimulation. Epac1 was localized in the perinuclear region. Epac2 showed little or no expression. The TSH-induced activation of Rap1 was presumably mediated by Epac1 because it was mimicked by the Epac-selective cAMP analog (8-p-chloro-phenyl-thio-2′-O-methyl-cAMP) and not by PKA-selective cAMP analogs. Surprisingly, in view of the high Epac1 expression and its TSH responsiveness, all the cAMP-dependent functions of TSH in cultures or tissue incubations of dog thyroid, in...