A molecular signature in the pannexin1 intracellular loop confers channel activation by the α1 adrenoreceptor in smooth muscle cells

Both purinergic signalingthrough nucleotides such as ATP ( adenosine 5′- triphosphate) and noradrenergic signaling through molecules such as norepinephrine regulate vascular tone and blood pressure. Pannexin1 (Panx1), which forms large-pore, ATP-releasing channels, is present in vascular smooth muscle cells in peripheral blood vessels and participates in noradrenergic responses. Using pharmacological approaches and mice conditionally lacking Panx1 in smooth muscle cells, we found that Panx1 contributed to vasoconstrictionmediated by the α1 adrenoreceptor (α1AR), whereas vasoconstrictionin response to serotonin or endothelin-1was independent of Panx1. Analysis of the Panx1-deficient mice showed that Panx1 contributed to blood pressure regulationespecially during the night cycle when sympathetic nervous activity is highest. Using mimetic peptides and site-directed mutagenesis, we identified a specific amino acid sequence in the Panx1 intracellular loop that is essential for activation by α1AR signaling. Collectively, these data describe a specific link between noradrenergic and purinergic signalingin blood pressure homeostasis.