Hypertension is a cardiovascular disease associated with increased plasma catecholamines, overactivation of the sympathetic nervous system, and increased vascular tone and total peripheral resistance. A key regulator of sympathetic nervous system function is the _1D-adrenergic receptor (AR), which belongs to the adrenergic family of G-protein coupled receptors (GPCRs). Endogenous catecholamines norepinephrine and epinephrine activate _1D-ARs on vascular smooth muscle to stimulate vasoconstriction, which increases total peripheral resistance and mean arterial pressure. Indeed, _1D-AR KO mice display a hypotensive phenotype and are resistant salt-induced hypertension. Unfortunately, little information exists about how this important GPCR functions, because of an inability to obtain functional expression in vitro. Here, we identified the dystrophin proteins, syntrophin, dystrobrevin and utrophin, as essential GPCR interacting proteins (GIPs) for _1D-ARs. We found dystrophins complex with _1D-AR both in vitro and in vivo to ensure proper functional expression. More importantly, we demonstrate knock-out of multiple syntrophin isoforms results in the complete loss of _1D-AR function in mouse aortic smooth muscle cells and abrogation of _1D-AR mediated increases in blood pressure. Our findings demonstrate that syntrophin and utrophin associate with _1D-ARs to create a functional signalosome, which is essential for _1D-AR regulation of vascular tone and blood pressure.