Multiple second messenger pathways of α-adrenergic receptor subtypes expressed in eukaryotic cells

The α-adrenergic receptors mediate the effects of epinephrine and norepinephrine on cellular signaling systems via guanine nucleotide binding regulatory proteins (G-proteins). Three α-adrenergic receptor subtypes have been cloned: the α₁, the α₂-C10, and the α₂-C4 adrenergic receptors. To investigate functional differences between the different subtypes, we assessed the ability of each to interact with adenylyl cyclase and polyphosphoinositide metabolism by permanently and transiently expressing the DNAs encoding the α₁, the α₂-C10, and the α₂-C4 adrenergic receptors in cells lacking endogenous α-adrenergic receptors. Both α₂-C10 and α₂-C4 couple primarily to inhibition of adenylyl cyclase and to a lesser extent to stimulation of polyphosphoinositide hydrolysis. α₂-C10 inhibits adenylyl cyclase more efficiently than α₂-C4. Effects of the α₂-adrenergic receptors on adenylyl cyclase inhibition and on polyphosphoinositide hydrolysis are both mediated by pertussis toxin-sensitive G-proteins. The major coupling system of the α₁-adrenergic receptor is activation of phospholipase C via a pertussis toxin-insensitive G-protein. α₁-Adrenergic receptor stimulation can also increase intracellular cAMP by a mechanism that does not involve direct activation of adenylyl cyclase. As with the muscarinic cholinergic receptor family our results show that each of the aα-adrenergic receptor subtypes can couple to multiple signal transduction pathways and suggest several generalities about the effector coupling mechanisms of G-protein-coupled receptors.