Endothelin (ET)-1 is involved in various diseases, including cancer, hypertension, atherosclerosis, diabetes, and fibrotic diseases, although ET-1 is originally identified as endothelium-derived vasocontractile peptide. ET receptors belong to the class A of G protein-coupled receptor, and consist of ET type A receptor (ETAR) and ET type B receptor (ETBR). ETAR and ETBR generally exhibit the opposite responses, although many exceptions exist. Here, we attempted to identify ETAR or ETBR specific binding proteins to understand difference of ETAR- and ETBR-mediated responses upon ET-1 stimulation. We found that GRP78 exhibited a stronger binding affinity toward ETBR than ETAR. Overexpression of GRP78 promotes ETBR-mediated ERK activation. In addition, the silencing of GRP78 suppressed ETBR-mediated ERK activation. On the other hand, ETBR can localize GRP78 to cell periphery. Our results suggest that interaction of ETBR with GRP78 affects the ERK activation and GRP78 localization.