Angiotensin II (Ang II) AT1 receptors, similar to other G protein-coupled receptors, undergo desensitization and internalization, and potentially nuclear localization, subsequent to agonist interaction. Evidence suggests that the carboxy-terminal tail may be involved in receptor nuclear localization. In the present study, we examined the carboxy-terminal tail of the receptor for specific regions responsible for the nuclear translocation phenomenon and resultant nuclear activation. Human embryonic kidney cells (HEK-293) stably expressing either a wild type AT_1A Receptor-Green Fluorescent Protein (AT_1AR/GFP) construct or a site-directed mutation of a putative nuclear localization sequence (NLS) [K307Q]AT_1AR/GFP (KQ/AT_1AR/GFP), were examined for differences in receptor nuclear trafficking and nuclear activation. Receptor expression, intracellular signaling and Ang II-induced internalization of the wild type/GFP construct and of the KQ/AT_1AR/GFP mutant was similar. Laser scanning confocal microscopy showed that in cells expressing the AT_1AR/GFP, trafficking of the receptor to the nuclear area and colocalization with lamin-B occurred within 30 minutes of Ang II (100 nM) stimulation, whereas, the KQ/AT_1AR/GFP mutant failed to demonstrate nuclear localization. Immunoblotting of nuclear lysates with an anti-GFP antibody confirmed these observations. Nuclear localization of the wild type receptor correlated with increase transcription for both EGR-1 and PTGS-2 genes while the nuclear-deficient KQ/AT_1AR/GFP mutant demonstrated increases for only the EGR-1 gene. These results suggest that a NLS (KKFKKY; aa307-312) is located within the cytoplasmic tail of the AT_1A receptor and that nuclear localization of the receptor corresponds with specific activation of transcription for the COX-2 gene PTGS-2.