β2-Adenoceptor activity antagonises vasoconstrictor-mediated vascular smooth muscle migration via an EPAC-, GRK5- and arrestin3-dependent mechanism.

We have investigated the signal transduction mechanisms linking β2-adrenoceptor activation to extracellular signal-regulated kinase1/2 (ERK) activity and cell migration in vascular smooth muscle, with a focus on the roles played by G protein-coupled receptor kinases (GRKs) and arrestin proteins in these processes. Activation of β2-adrenoceptors in rat aortic smooth muscle (RASM) cells caused a time- and concentration-dependent suppression of basal phospho-ERK (pERK), and this effect was recapitulated by direct activation of adenylyl cyclase activity by forskolin. Activation of β2-adrenoceptors also inhibited the abilities of vasoconstrictors (angiotensin II, endothelin-1 and uridine 5'-triphosphate) to stimulate ERK phosphorylation. Using a variety of pharmacological and genetic approaches it was shown that the ability of β2-adrenoceptor activation to suppress ERK phosphorylation was exchange protein directly activated by cAMP (EPAC) (and not Protein kinase A, PKA), GRK5 and arrestin3-dependent. We have also shown that the ability of β2-adrenoceptor activation to attenuate vasoconstrictor-induced RASM cell migration is mediated by similar (EPAC-, GRK5- and arrestin3-dependent) signal transduction pathways. Finally, we report that the ability of β2-adrenoceptor activation to suppress ERK phosphorylation and to attenuate vasoconstrictor-induced cell migration is lost in RASM cells isolated from hypertensive spontaneously hypertensive rats (SHR), but not normotensive Wistar-Kyoto (WKY) rats. Our studies reveal an unexpected pathway linking the β2-adrenoceptor to the regulation of extracellular-signal regulated kinase (ERK) activity and cell migration in aortic smooth muscle cells.