A polymorphism-specific "memory" mechanism in the ß(2)-adrenergic receptor.

ABSTRACT

Signaling through G protein (heterotrimeric guanosine triphosphate-binding protein)-coupled receptors is affected by polymorphisms in receptor-encoding genes. Using fluorescence resonance energy transfer, we found that the ß(2)-adrenergic receptor (ß(2)AR) responded to repeated activation with altered activation kinetics. Polymorphic variants of the ß(2)AR displayed divergent changes of ß(2)AR activation kinetics that closely mimicked their different efficacies to generate cyclic adenosine 3',5'-monophosphate. More efficacious variants became faster in their activation kinetics, whereas less efficacious variants became slower, compared to their initial activation. These differences depended on phosphorylation of the receptor by G protein-coupled receptor kinases. Our findings suggest an intrinsic, polymorphism-specific property of the ß(2)AR that alters activation kinetics upon continued stimulation and that may account for individual drug responses.