Document Detail

Functional diversity of AT2 receptor orthologues in closely related species.
MedLine Citation:
PMID:  15840019     Owner:  NLM     Status:  MEDLINE    
BACKGROUND: The most striking feature of life is biodiversity. However, mechanisms of biodiversity remain poorly understood, as most protein orthologues of different species are highly homologous in sequence and identical in function. Interestingly, recent evidence has demonstrated heterogeneity for a G protein-coupled angiotensin II (Ang II) type 2 (AT(2)) receptor in both ligand binding and induction of arachidonic acid (AA) release. The present study investigated the properties of AT(2) receptors in closely related species.
METHODS: AT(2) receptors cloned from human, rabbit, rat, and mouse were expressed in Chinese hamster ovary cells (CHO-K1), African green monkey kidney cells (COS-1), and human embryonic kidney (HEK)-293 cells and characterized in ligand binding and signal transductions. Critical residues in rabbit AT(2) receptor attributable to heterogeneity were examined using both gain-of-function and loss-of-function approaches with mutagenesis.
RESULTS: The newly cloned rabbit AT(2) receptor exhibits distinct biochemical and biologic properties compared to its highly homologous orthologues (91% in overall amino acid sequence) of rat, mouse, and human. All these orthologues activate SH2 domain-containing phosphatase-1 (SHP-1) and show similar binding affinities for Ang II and AT(2)-specific ligands CGP42112A and PD123319. However, reducing agent dithiothreitol (DTT) inactivates the rabbit orthologue but potentiates the others in ligand binding, a hallmark of AT(2) versus AT(1) receptor subtypes. Most interestingly, rabbit AT(2) receptor, but not the other orthologues, induces AA release in various cell systems when stimulated by both Ang II and CGP42112A, the peptide antagonist. Mutagenesis studies and sequence analyses further indicate that residues His(106), Asp(188), and Thr(293) are responsible for the DTT inactivation and residues Val(209) and Val(249) are partially responsible for AA release.
CONCLUSION: These results deny the coexistence of an additional AT(2) subtype in rabbit proximal tubule cells and demonstrate for the first time the presence of functional diversity for closely related Eutherian orthologues of a G protein-coupled receptor (GPCR) that are more than 90% homologous in the amino acid sequence.
Ying-Hong Feng; Lingyin Zhou; Yan Sun; Janice G Douglas
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Publication Detail:
Type:  Comparative Study; Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, P.H.S.    
Journal Detail:
Title:  Kidney international     Volume:  67     ISSN:  0085-2538     ISO Abbreviation:  Kidney Int.     Publication Date:  2005 May 
Date Detail:
Created Date:  2005-04-20     Completed Date:  2005-08-22     Revised Date:  2013-06-09    
Medline Journal Info:
Nlm Unique ID:  0323470     Medline TA:  Kidney Int     Country:  United States    
Other Details:
Languages:  eng     Pagination:  1731-8     Citation Subset:  IM    
Department of Pharmacology, Uniformed Services University of the Health Sciences, Bethesda, Maryland 20814, USA.
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MeSH Terms
Amino Acid Sequence
Amino Acid Substitution
Arachidonic Acid / metabolism
Base Sequence
Binding Sites / genetics
CHO Cells
COS Cells
Cell Line
Cercopithecus aethiops
Cloning, Molecular
DNA, Complementary / genetics
Dithiothreitol / pharmacology
Intracellular Signaling Peptides and Proteins
Molecular Sequence Data
Mutagenesis, Site-Directed
Protein Phosphatase 1
Protein Tyrosine Phosphatase, Non-Receptor Type 6
Protein Tyrosine Phosphatases / metabolism
Receptor, Angiotensin, Type 2 / genetics,  metabolism*
Recombinant Proteins / genetics,  metabolism
Sequence Homology, Amino Acid
Species Specificity
Grant Support
Reg. No./Substance:
0/DNA, Complementary; 0/Intracellular Signaling Peptides and Proteins; 0/Ligands; 0/Receptor, Angiotensin, Type 2; 0/Recombinant Proteins; 3483-12-3/Dithiothreitol; 506-32-1/Arachidonic Acid; EC Phosphatase 1; EC protein, human; EC Tyrosine Phosphatase, Non-Receptor Type 6; EC Tyrosine Phosphatases; EC protein, mouse; EC protein, rat

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