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 α 2A -adrenergic receptor knockout mice suggested that the α 2A -receptor subtype inhibits neurotransmitter release with higher speed and at higher action potential frequencies than the α 2C -adrenergic receptor. Here we investigated whether these functional differences between presynaptic α 2 -adrenergic receptor subtypes are the result of distinct signal transduction kinetics of these two receptors and their coupling to G proteins. α 2A - and α 2C -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 α 2A - and α 2C -receptors at both expression levels. However, the two receptors differed significantly in their deactivation kinetics after removal of the agonist norepinephrine. α 2C -Receptor-activated GIRK currents returned much more slowly to base line than did α 2A -stimulated currents. This observation correlated with a higher affinity of norepinephrine at the murine α 2C - than at the α 2A -receptor subtype and may explain why α 2C -adrenergic receptors are especially suited to control sympathetic neurotransmission at low action potential frequencies in contrast to the α 2A -receptor subtype.