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J. Biol. Chem., Vol. 269, Issue 40, 24692-24698, Oct, 1994
ME Olah, KA Jacobson and GL Stiles
Adenosine receptor (AR) agonists and antagonists are approximately 100-
fold and 100,000-fold, respectively, more potent at the bovine A1AR as
compared to the rat A3AR. To determine regions of ARs involved in ligand
recognition, chimeric receptors composed of bovine A1AR and rat A3AR
sequence were constructed and their ligand binding properties examined
following expression in COS-7 cells. Substitutions of the second
extracellular loop or a region encompassing transmembrane domains 6 and 7
of the A1AR into the A3AR resulted in enhanced affinities of both agonists
and antagonists compared to wild-type A3AR. The region of the second
extracellular loop of the A1AR responsible for this effect was identified
as the distal eleven amino acids of the loop. Replacement of this segment
of the A3AR with that of the A1AR in combination with the regions
encompassing transmembrane domains 6 and 7 resulted in a 50,000-fold
increase in the Kd for antagonist radioligand, [3H]1,3-dipropyl-8-
cyclopentylxanthine. Agonist affinity at this chimeric was over 100-fold
greater than that displayed by wild- type A3AR. Thus, multiple regions of
ARs including a segment of the second extracellular loop are involved in
ligand recognition, and considerable overlap exists in structural features
required for agonist and antagonist binding.
Role of the second extracellular loop of adenosine receptors in agonist and antagonist binding. Analysis of chimeric A1/A3 adenosine receptors
Department of Medicine, Duke University Medical Center, Durham, North Carolina 27710.
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