Angiotensin II (angII) is the major effector molecule of the renin angiotensin system and a principal determinant of blood pressure and fluid volume. Progress towards an understanding of the molecular properties of receptors for angII (AT receptors) has lagged that achieved for other components of the renin-angiotensin system. Although evidence of AT receptor heterogeneity has accumulated over two decades, progress towards defining an AT receptor family has been hindered by a lack of information on receptor primary structure. On the basis of newly developed nonpeptidic ligands, the existence of two classes of AT receptors, termed AT1 and AT2, has been proposed. However, no known biological response has been associated with AT2 binding sites. Thus, its existence could not have been predicted by earlier studies. Therefore, diversity within the AT1 receptor class most likely accounts for early evidence of AT receptor heterogeneity. A cDNA encoding a rat vascular smooth muscle AT1 receptor has now been isolated. the amino acid sequence encoded by this clone shares seven hydrophobic, putative membrane spanning structures and conserved amino acid motifs with the rhodopsin-like superfamily of G-protein-coupled receptors. Genomic Southern analysis demonstrates several hybridizing bands to a cloned cDNA probe that suggests the possibility of molecular diversity in AT1 receptors. The objective of this proposal is to define rigorously the molecular basis for this diversity by isolating cDNAs and/or genes encoding additional AT1 receptor subtypes. Using a model system whereby each cloned receptor is uniquely transfected and expressed in a cell line, their pharmacological attributes and biochemical signalling mechanisms will be studied in the absence of AT receptor heterogeneity commonly found in other tissue models. Experiments are proposed to localize the tissue and cellular distribution of AT1 receptor subtypes using in situ hybridization and immuno-cytochemical approaches. These studies should improve knowledge of the pharmacology, function and distribution of AT receptors subtypes. They should improve the rational development of selective therapeutic agents for the treatment of cardiovascular disorders, and provide insights into potential pathophysiological roles of AT receptors.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
First Independent Research Support & Transition (FIRST) Awards (R29)
Project #
5R29HL048252-02
Application #
3473867
Study Section
Cardiovascular and Renal Study Section (CVB)
Project Start
1992-04-01
Project End
1996-03-31
Budget Start
1993-04-01
Budget End
1994-03-31
Support Year
2
Fiscal Year
1993
Total Cost
Indirect Cost
Name
Emory University
Department
Type
Schools of Medicine
DUNS #
042250712
City
Atlanta
State
GA
Country
United States
Zip Code
30322
Wang, X; Nickenig, G; Murphy, T J (1997) The vascular smooth muscle type I angiotensin II receptor mRNA is destabilized by cyclic AMP-elevating agents. Mol Pharmacol 52:781-7
Boss, V; Talpade, D J; Murphy, T J (1996) Induction of NFAT-mediated transcription by Gq-coupled receptors in lymphoid and non-lymphoid cells. J Biol Chem 271:10429-32
Nickenig, G; Murphy, T J (1996) Enhanced angiotensin receptor type 1 mRNA degradation and induction of polyribosomal mRNA binding proteins by angiotensin II in vascular smooth muscle cells. Mol Pharmacol 50:743-51
Lassegue, B; Alexander, R W; Nickenig, G et al. (1995) Angiotensin II down-regulates the vascular smooth muscle AT1 receptor by transcriptional and post-transcriptional mechanisms: evidence for homologous and heterologous regulation. Mol Pharmacol 48:601-9
Esbenshade, T A; Hirasawa, A; Tsujimoto, G et al. (1995) Cloning of the human alpha 1d-adrenergic receptor and inducible expression of three human subtypes in SK-N-MC cells. Mol Pharmacol 47:977-85
Venema, R C; Nishida, K; Alexander, R W et al. (1994) Organization of the bovine gene encoding the endothelial nitric oxide synthase. Biochim Biophys Acta 1218:413-20
Nickenig, G; Murphy, T J (1994) Down-regulation by growth factors of vascular smooth muscle angiotensin receptor gene expression. Mol Pharmacol 46:653-9
Takeuchi, K; Alexander, R W; Nakamura, Y et al. (1993) Molecular structure and transcriptional function of the rat vascular AT1a angiotensin receptor gene. Circ Res 73:612-21
Murphy, T J; Nakamura, Y; Takeuchi, K et al. (1993) A cloned angiotensin receptor isoform from the turkey adrenal gland is pharmacologically distinct from mammalian angiotensin receptors. Mol Pharmacol 44:1-7
Esbenshade, T A; Han, C; Murphy, T J et al. (1993) Comparison of alpha 1-adrenergic receptor subtypes and signal transduction in SK-N-MC and NB41A3 neuronal cell lines. Mol Pharmacol 44:76-86

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