Assembly of a Β 2-adrenergic receptorGluR1 signalling complex for localized cAMP signalling

Central noradrenergic signalling mediates arousal and facilitates learning through unknown molecular mechanisms. Here, we show that the Β 2-adrenergic receptor (Β 2 AR), the trimeric G s protein, adenylyl cyclase, and PKA form a signalling complex with the AMPA-type glutamate receptor subunit GluR1, which is linked to the Β 2 AR through stargazin and PSD-95 and their homologues. Only GluR1 associated with the Β 2 AR is phosphorylated by PKA on Β 2 AR stimulation. Peptides that interfere with the Β 2 AR-GluR1 association prevent this phosphorylation of GluR1. This phosphorylation increases GluR1 surface expression at postsynaptic sites and amplitudes of EPSCs and mEPSCs in prefrontal cortex slices. Assembly of all proteins involved in the classic Β 2 AR-cAMP cascade into a supramolecular signalling complex and thus allows highly localized and selective regulation of one of its major target proteins.