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 alpha (2A)-adrenergic receptor knockout mice suggested that the alpha (2A)-receptor subtype inhibits neurotransmitter release with higher speed and at higher action potential frequencies than the a,c-adrenergic receptor. Here we investigated whether these functional differences between presynaptic alpha (2)-adrenergic receptor subtypes are the result of distinct signal transduction kinetics of these two receptors and their coupling to G proteins. alpha (2A)- and alpha (2C)-receptors were stably expressed in HEK293 cells at moderate (similar to2 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 alpha (2A)- and alpha (2C)-receptors at both expression levels. However, the two receptors differed significantly in their deactivation kinetics after removal of the agonist norepinephrine. alpha (2C)-Receptor-activated GIRK currents returned much more slowly to base line than did alpha (2A)-stimulated currents. This observation correlated with a higher affinity of norepinephrine at the murine alpha (2C)- than at the alpha (2A)-receptor subtype and may explain why alpha (2C)-adrenergic receptors are especially suited to control sympathetic neurotransmission at low action potential frequencies in contrast to the alpha (2A)-receptor subtype.