We investigated the effects of AT-I receptor stimulation by angiotensin II (Ang II) on human ether-a-go-go-related gene (hERG) potassium channel protein in a heterogeneous expression system with the human embryonic kidney (HEK) 293 cells which stably expressed hERG channel protein and were transiently transfected with the human AT(1) receptors (HEK293/hERG). Western-blot analysis showed that Ang II significantly decreased the expression of mature hERG channel protein (155-kDa band) in a time- and dose-dependent manner without affecting the level of immature hERG channel protein (135-kDa band). The relative intensity of 155-kDa band was 64.7 +/- 6.8% of control (P < 0.01) after treatment of Ang II at 100 nM for 24 h. To investigate the effect of Ang II on the degradation of mature hERG channel protein, we blocked forward trafficking from ER to Golgi with a Golgi transit inhibitor brefeldin A (10 mu M). Ang II significantly enhanced the time-dependent reduction of mature hERG channel protein. In addition, the proteasomal inhibitor lactacystin (5 mu M) inhibited Ang II-mediated the reduction of mature hERG channel protein, but the lysosomal inhibitor bafilomycin A1 (1 mu M) had no effect on the protein. The protein kinase C (PKC) inhibitor bisindolylmaleimide 1 (1 mu M) antagonized the reduction of mature hERG channel protein induced by Ang II. The results indicate that sustained stimulation of AT(1) receptors by Mg II reduces the mature hERG channel protein via accelerating channel proteasomal degradation involving the PKC pathway. (C) 2014 Elsevier Inc. All rights reserved.