Regulation of pharmacology by hetero-oligomerization between A1 adenosine receptor and P2Y2 receptor.
Adenosine and ATP/UTP are main components of the purinergic system that modulate cellular and tissue functions via specific adenosine and P2 receptors, respectively. Here, we explored the possibility that A(1) adenosine receptor (A(1)R) and P2Y(2) receptor (P2Y(2)R) form heterodimers with novel pharmacological properties. Coimmunoprecipitation showed these receptors directly associate in A(1)R/P2Y(2)R-cotransfected HEK293T cells. Agonist binding by the A(1)R was significantly inhibited by P2Y(2)R agonists only in membranes from cotransfected cells. The functional activity of A(1)R, as indicated by the G(i/o)-mediated inhibition of adenylyl cyclase, in the cotransfected cells was attenuated by the simultaneous addition of A(1)R and P2Y(2)R agonists. The increase in intracellular Ca(2+) levels induced by P2Y(2)R activation of G(q/11) was synergistically enhanced by the simultaneous addition of an A(1)R agonist in the coexpressing cells. These results suggest that oligomerization of A(1)R and P2Y(2)R generates a unique complex in which the simultaneous activation of the two receptors induces a structural alteration that interferes signaling via G(i/o) but enhances signaling via G(q/11).
Suzuki
Tokiko
T
Department of Molecular Cell Signaling, Tokyo Metropolitan Institute for Neuroscience, 2-6 Musashidai, Fuchu, Tokyo 183-8526, Japan.
Namba
Kazunori
K
Tsuga
Hirofumi
H
Nakata
Hiroyasu
H
D058907:Adenosine A1 Receptor Agonists; D019830:Adenosine-5'-(N-ethylcarboxamide) / Q000494:pharmacology; D000818:Animals; D002118:Calcium / Q000378:metabolism*; D002460:Cell Line; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism*; D003001:Cloning, Molecular; D000242:Cyclic AMP / Q000378:metabolism; D006801:Humans; D011485:Protein Binding; D058910:Purinergic P2 Receptor Agonists; D051381:Rats; D043682:Receptor, Adenosine A1 / Q000378:metabolism*; D018048:Receptors, Purinergic P2 / Q000378:metabolism*; D058473:Receptors, Purinergic P2Y2; D014544:Uridine Triphosphate / Q000494:pharmacology; D014970:Xanthines / Q000494:pharmacology
D058907:Adenosine A1 Receptor Agonists; C546385:P2RY2 protein, human; D058910:Purinergic P2 Receptor Agonists; D043682:Receptor, Adenosine A1; D018048:Receptors, Purinergic P2; D058473:Receptors, Purinergic P2Y2; D014970:Xanthines; D019830:Adenosine-5'-(N-ethylcarboxamide); C051360:1,3-dipropyl-8-cyclopentylxanthine; D000242:Cyclic AMP; D002118:Calcium; D014544:Uridine Triphosphate