Pharmacological characterization of the porcine atrial A₁ adenosine receptor Public Deposited

http://ir.library.oregonstate.edu/concern/graduate_thesis_or_dissertations/jh343x707

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  • Cardiac A₁ adenosine receptors mediate cardioinhibitory properties of adenosine and structural congeners. The objective of these studies was to increase our understanding of molecular processes involved in ligand interactions with receptors mediating cardioinhibitory effects of adenosine and the interactions of these receptors with guanine nucleotide binding regulatory proteins. Porcine atrial A₁ receptors receptors were characterized using both agonist (N⁶-(3- [¹²⁵I]iodo-4-hydroxyphenylisopropyl)adenosine, [¹²⁵I]HPIA) and antagonist (8-cyclopentyl- 1,3[³H]dipropyl xanthine, [³H]DPCPX) radioligands. [³H]DPCPX was shown to be the first useful antagonist radioligand for labeling atrial Al adenosine receptors. The atrial adenosine receptor displayed two agonist affinity states: a guanine nucleotide-sensitive high affinity state and a guanine nucleotideinsensitive low affinity state. The former was demonstrated to be entirely the result of ternary complex formation in porcine atrial membranes (agonist-receptor-G protein). [¹²⁵I]HPIA labeled a homogeneous population of membrane-bound atrial A₁ adenosine receptors which appeared to exist pre-coupled (in the absence of agonist) to a guanine nucleotide binding protein. Guanine nucleotides negatively modulated [¹²⁵I]HPIA binding by increasing the rate of dissociation of the agonist radioligand, providing direct evidence for ternary complex formation in porcine atrial membranes. Solubilization of atrial adenosine receptors using a mixed detergent system (digitonin/sodium cholate) resulted in a 2.5-fold enrichment of adenosine receptor specific activity over that of porcine atrial membrane preparations. Both pharmacological specificity and receptor-G protein interactions were preserved in detergent solution. [¹²⁵I]HPIA interacted via a simple bimolecular reaction with solubilized atrial adenosine receptors that existed precoupled to G protein(s). Guanine nucleotide-initiated [¹²⁵I]HPIA dissociation was biphasic and appeared to arise from independent, non-interconvertible populations of receptor-G protein complexes. Thus, kinetic evidence indicates that the atrial adenosine receptor is able to couple to two distinct G proteins in detergent solution.
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