Activation and Deactivation Kinetics of α2A- and α2C-Adrenergic Receptor-activated G Protein-activated Inwardly Rectifying K+ Channel Currents

Although G protein-coupled receptor-mediated signaling is one of the best studied biological events, little is known about the kinetics of these processes in intact cells. Experiments with neurons from α2A-adrenergic receptor knockout mice suggested that the α2A-receptor subtype inhibits neurotransmitter release with higher speed and at higher action potential frequencies than the α2C-adrenergic receptor. Here we investigated whether these functional differences between presynaptic α2-adrenergic receptor subtypes are the result of distinct signal transduction kinetics of these two receptors and their coupling to G proteins. α2A- and α2C-receptors were stably expressed in HEK293 cells at moderate (∼2 pmol/mg) or high (17–24 pmol/mg) levels. Activation of G protein-activated inwardly rectifying K+ (GIRK) channels was similar in extent and kinetics for α2A- and α2C-receptors at both expression levels. However, the two receptors differed significantly in their deactivation kinetics after removal of the agonist norepinephrine. α2C-Receptor-activated GIRK currents returned much more slowly to base line than did α2A-stimulated currents. This observation correlated with a higher affinity of norepinephrine at the murine α2C- than at the α2A-receptor subtype and may explain why α2C-adrenergic receptors are especially suited to control sympathetic neurotransmission at low action potential frequencies in contrast to the α2A-receptor subtype.