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Plasma membrane ion channels modulate the physiological functions of virtually all cell types, including vascular smooth muscle cells (myocytes) [1]. Many ion channels are composed of both pore-forming and auxiliary subunits, with the conventional view that these proteins coassemble intracellularly prior to anterograde surface trafficking of the multi-protein complex. Recent work in our laboratory has shown that surface ion channel subunit composition is flexible and can be modulated to control activity and cellular function in arterial myocytes [2-5]. Membrane potential is a key regulator of arterial contractility [6]. Membrane depolarization activates voltage-dependent Ca2+ channels in arterial smooth muscle cells, leading to Ca2+ influx, an increase in intracellular Ca2+ concentration and vasoconstriction [6]. In contrast, membrane hyperpolarization reduces intracellular Ca2+ concentration, leading to vasodilation. Arterial smooth muscle cells express large-conductance Ca2+-activated (BK) potassium channels, which are a homotetramer of pore-forming α subunits (BKα) that can couple to auxiliary β1 subunits that modify channel activity [7]. BK channel activation leads to membrane hyperpolarization and vasodilation, whereas BK channel inhibition results in vasoconstriction [6, 7]. BK channels are activated by several different stimuli, including an increase in intracellular Ca2+ concentration and physiological vasodilators such as nitric oxide [7]. In contrast, vasoconstrictors, including angiotensin II and endothelin-1, inhibit BK channels [6]. Previous studies have primarily investigated mechanisms that regulate the activity of surface-resident BK channels. In contrast, only recently has evidence emerged that physiological stimuli also control the surface abundance of BK channel subunits to modulate arterial myocyte contractility. The current (I) generated by an ion channel population is the product of the number of channels (N), open probability (PO) and single channel current (i), such that: I=N.PO.i. Earlier studies focused on identifying mechanisms that control PO in arterial myocytes. In contrast, pathways that regulate the number of ion channel subunits in the plasma membrane (N) remained unclear. Our research in rat and human arterial myocytes was the first to show that BK channel subunit composition is dynamic and modulated by physiological stimuli to control channel activity (Figure 1). In arterial myocytes, BKα subunits are primarily (>95 %) plasma membrane localized, whereas only a small fraction (<10%) of total β1 subunits are present at the cell surface [2]. BKα and β1 subunits are each trafficked by distinct pathways in arterial myocytes. BKα subunits are localized within and surface trafficked by rab4A-positive early endosomes (Figure 1) [3]. In contrast, β1 subunits are stored within rab11A-positive recycling endosomes and are surfacetrafficked in response to specific stimuli [2]. We have shown that NO, through the activation of protein kinase G (PKG), and protein kinase A (PKA), stimulate rapid (≤1 min) surface trafficking of β1 subunits which then associate with BKα subunits present at the cell membrane [2]. β1 is constantly recycled and NO stimulates PKGmediated phosphorylation of rab11A to increase β1 surface abundance (Figure 1). The increase in surface β1 subunits elevates the apparent Ca2+-sensitivity of BK channels, leading to activation and vasodilation [2]. Intravascular pressure stimulates arterial depolarization and activates BK channels [6]. It was unclear if membrane potential controlled BK currents by modulating surface trafficking of β1 subunits. Recently, Editorial

Trafficking of BK channel subunits controls arterial contractility