Adenosine A1 receptors heterodimerize with β1- and β2-adrenergic receptors creating novel receptor complexes with altered G protein coupling and signaling. Cell Signal 2013 Apr;25(4):736-42
Date
01/08/2013Pubmed ID
23291003Pubmed Central ID
PMC3896953DOI
10.1016/j.cellsig.2012.12.022Scopus ID
2-s2.0-84873252073 (requires institutional sign-in at Scopus site) 34 CitationsAbstract
G protein coupled receptors play crucial roles in mediating cellular responses to external stimuli, and increasing evidence suggests that they function as multiple units comprising homo/heterodimers and hetero-oligomers. Adenosine and β-adrenergic receptors are co-expressed in numerous tissues and mediate important cellular responses to the autocoid adenosine and sympathetic stimulation, respectively. The present study was undertaken to examine whether adenosine A1ARs heterodimerize with β1- and/or β2-adrenergic receptors (β1R and β2R), and whether such interactions lead to functional consequences. Co-immunoprecipitation and co-localization studies with differentially epitope-tagged A1, β1, and β2 receptors transiently co-expressed in HEK-293 cells indicate that A1AR forms constitutive heterodimers with both β1R and β2R. This heterodimerization significantly influenced orthosteric ligand binding affinity of both β1R and β2R without altering ligand binding properties of A1AR. Receptor-mediated ERK1/2 phosphorylation significantly increased in cells expressing A1AR/β1R and A1AR/β2R heteromers. β-Receptor-mediated cAMP production was not altered in A1AR/β1R expressing cells, but was significantly reduced in the A1AR/β2R cells. The inhibitory effect of the A1AR on cAMP production was abrogated in both A1AR/β1R and A1AR/β2R expressing cells in response to the A1AR agonist CCPA. Co-immunoprecipitation studies conducted with human heart tissue lysates indicate that endogenous A1AR, β1R, and β2R also form heterodimers. Taken together, our data suggest that heterodimerization between A1 and β receptors leads to altered receptor pharmacology, functional coupling, and intracellular signaling pathways. Unique and differential receptor cross-talk between these two important receptor families may offer the opportunity to fine-tune crucial signaling responses and development of more specific therapeutic interventions.
Author List
Chandrasekera PC, Wan TC, Gizewski ET, Auchampach JA, Lasley RDAuthors
John A. Auchampach PhD Professor in the Pharmacology and Toxicology department at Medical College of WisconsinTina C. Wan PhD Research Scientist II in the Pediatrics department at Medical College of Wisconsin
MESH terms used to index this publication - Major topics in bold
Adenosine A1 Receptor AgonistsCyclic AMP
Dimerization
HEK293 Cells
Humans
Mitogen-Activated Protein Kinase 1
Mitogen-Activated Protein Kinase 3
Myocardium
Phosphorylation
Protein Binding
Receptor, Adenosine A1
Receptors, Adrenergic, beta-1
Receptors, Adrenergic, beta-2
Receptors, G-Protein-Coupled
Recombinant Proteins
Signal Transduction
Transfection
