Cross‐talk between beta and alpha2 adrenergic receptors in sympathetic neurons relies on protein kinase A and spinophilin

Physiological overlap between β and α 2 adrenergic receptors (ARs) in the sympathetic nervous system raises the possibility that adrenergic therapeutics targeting one AR may influence the function of other ARs. The present study is therefore aimed at investigating whether and through what mechanism clinically‐relevant βAR ligands can influence α 2A AR responses in noradrenergic sympathetic neurons. Our previous work has established the dendritic scaffolding protein spinophilin (Sp) as a key regulator of α 2A AR responses. As well, we have shown that protein kinase A (PKA) phosphorylation of Sp prevents its interaction with the α 2A AR, providing a potential avenue for crosstalk with the Gs‐coupled, PKA‐activating βARs. In the present study, we show that βAR agonists accelerate α 2 AR agonist‐mediated α 2A AR internalization and enhance α 2A AR MAP kinase signaling response sensitivity in primary sympathetic neurons. Importantly, these effects occur in a PKA‐dependent fashion. We further show that agonist‐mediated α 2A AR responses are accelerated/enhanced in Sp‐null neurons and that addition of βAR agonists has no additional effect in the Sp‐null system. Mechanistically, we show that agonist‐mediated α 2A AR/Sp interaction is attenuated by the addition of a βAR agonist. Our findings underscore the potential importance of AR cross‐talk to adrenergic pharmacology. Work supported by NIMH (MH081917).