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Adenosine A 1 and A 2A receptor effects on G‐protein cycling in β‐adrenergic stimulated ventricular membranes
Author(s) -
Fenton Richard A.,
Dobson James G.
Publication year - 2007
Publication title -
journal of cellular physiology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.529
H-Index - 174
eISSN - 1097-4652
pISSN - 0021-9541
DOI - 10.1002/jcp.21149
Subject(s) - ccpa , adenylyl cyclase , gtp' , chemistry , receptor , adenosine , agonist , allosteric regulation , cgs 21680 , pharmacology , medicine , adenosine receptor , endocrinology , biochemistry , biology , enzyme
In the heart β 1 ‐adrenergic (β1R) and adenosine A 1 (A1R) and A 2A (A2AR) receptors modulate contractile and metabolic function. The interaction between these receptors was investigated at the level of G‐protein cycling by determining the effect of receptor agonists on the binding of GTP to G‐proteins and displacement of Gα‐subunit‐bound GDP by GTP. Crude membranes from rat heart or brain were stimulated by agonists for β1R (isoproterenol; ISO), A1R (chlorocyclopentyladenosine, CCPA) and A2AR (CGS‐21680; CGS). GTP binding to membranes was increased by ISO (17%), CCPA (6%) and CGS (12%). Binding values observed with incubation using ISO and CCPA together were significantly less than values obtained by the incubation of individual agents alone. With ISO, GTP binding to Gα s subunits as determined by immunoprecipitation was increased 79% in heart and 87% in brain. These increases were attenuated by CCPA, an effect that was inhibited by CGS. GDP release by membranes was increased 6.9% and 4.6% by ISO and CCPA, respectively. After co‐incubation of these agonists, release was increased less than determined by the addition of the individual agent responses. CGS inhibited the reduced release caused by of CCPA. Adenylyl cyclase activity stimulated by ISO was attenuated 33% by CCPA, an effect inhibited by CGS. Together, these results indicate that A1R exert an antiadrenergic action at the level of β1R stimulated G s ‐protein cycling and that A2AR reduce this action. J. Cell. Physiol. 213:785–792. © 2007 Wiley‐Liss, Inc.