Dynamic regulation of β1 subunit trafficking controls vascular contractility

Abstract

Ion channels composed of pore‐forming and auxiliary subunits control physiological functions in virtually all cell types. Whether the multi‐subunit composition of surface channels is fixed following protein synthesis or flexible and open to acute and rapid modulation to control physiological cellular functions is unclear. Arterial myocytes express large‐conductance Ca2+‐activated potassium (BK) channel α and auxiliary β1 subunits that are functionally significant modulators of arterial contractility. Here, we show that native BK α subunits are primarily (~95%) plasma membrane‐localized, whereas only a small fraction (~10%) of total β1 subunits are located at the cell surface in human and rat arterial myocytes. Immuno‐FRET microscopy demonstrated that intracellular β1 subunits are stored within Rab11A‐postive recycling endosomes. Nitric oxide (NO), acting via protein kinase G, stimulated rapid (1 min) anterograde trafficking of β1 subunit‐containing endosomes. These β1 subunits associated with surface‐resident BKα proteins, elevating Ca2+‐sensitivity and inducing activation. Data also show that rapid β1 subunit anterograde trafficking is the primary mechanism by which NO activates myocyte BK channels and induces vasodilation. In summary, we show that rapid surface trafficking of β1 subunits controls functional BK channel activity in arterial myocytes and vascular contractility. Grant Funding Source: Supported by NIH‐HL67061

WNK1 Activates Large-Conductance Ca2+-Activated K+ Channels through Modulation of ERK1/2 Signaling

“…42 The b1 subunit itself can also rapidly traffic to the surface in response to nitric oxide stimulation and can activate the BKa channel. 25 However, it is not entirely clear whether the b subunit of the BK channel affects the internalization and degradation of BKa. BKa itself can traffic to the plasma …”

“…24 The b1 subunit rapidly traffics to surface membrane to associate with BKa and control functional BK activity in response to nitric oxide stimulation. 25 BKa is expressed in various renal tubular segments, including medullary and cortical thick ascending limbs, 26 distal convoluted tubule, 27 connecting tubule, 28 principal cells and intercalated cells of the cortical collecting duct (CCD). 29 BK channel is responsible for the flowdependent K + secretion in CCD.…”

Local coupling of TRPC6 to ANO1/TMEM16A channels in smooth muscle cells amplifies vasoconstriction in cerebral arteries

“…Percentage of weighted colocalization was calculated using Pascal system-embedded software. For normalized Förster resonance energy transfer (N-FRET) analysis, images were background-subtracted and N-FRET was calculated on a pixel-bypixel basis for the entire image and in regions of interest using the Xia method and Zeiss LSM FRET Macro tool version 2.5, as previously described (20).…”

High-fat diet-induced obesity alters nitric oxide-mediated neuromuscular transmission and smooth muscle excitability in the mouse distal colon

“…enteric nervous system; large conductance calcium-activated K ϩ channel; gastrointestinal motility; obesity A HIGH-FAT DIET (HFD) can cause obesity (35) that leads to an increased risk for the development of type 2 diabetes (13,17,33), heart disease (29, 33), and arthritis (25). Obesity is also associated with gastrointestinal (GI) dysmotility (15,35,41,63). GI motility is controlled largely by interactions between enteric neurons, interstitial cells of Cajal (ICCs), and smooth muscle cells (SMCs) but how obesity alters the function of these cells is poorly understood.…”

“…enteric nervous system; large conductance calcium-activated K ϩ channel; gastrointestinal motility; obesity A HIGH-FAT DIET (HFD) can cause obesity (35) that leads to an increased risk for the development of type 2 diabetes (13,17,33), heart disease (29,33), and arthritis (25). Obesity is also associated with gastrointestinal (GI) dysmotility (15,35,41,63).…”