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Am J Physiol Cell Physiol 292: C1398-C1408, 2007. First published December 13, 2006; doi:10.1152/ajpcell.00337.2006
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RECEPTORS AND SIGNAL TRANSDUCTION

Identification of a putative nuclear localization sequence within ANG II AT_1A receptor associated with nuclear activation

Divisions of Nephrology and Endocrinology, Department of Medicine, Medical University of South Carolina, and the Ralph H. Johnson Veterans Administration Hospital, Charleston, South Carolina

Submitted 19 June 2006 ; accepted in final form 5 December 2006

Angiotensin II (ANG II) type 1 (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 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 min 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.

G protein-coupled receptors; cyclooxygenase 2 transcription; laser scanning confocal microscopy

This article has been cited by other articles:

				X. C. Li and J. L. Zhuo Intracellular ANG II directly induces in vitro transcription of TGF-{beta}1, MCP-1, and NHE-3 mRNAs in isolated rat renal cortical nuclei via activation of nuclear AT1a receptors Am J Physiol Cell Physiol, April 1, 2008; 294(4): C1034 - C1045. [Abstract] [Full Text] [PDF]