Functional Proteomics of BK Potassium Channels: Defining the Acute Oxygen Sensor

Kemp, Paul J.; Williams, Sandile E; Mason, Helen S.; Wootton, Phillippa; Iles, David; Riccardi, Daniela; Peers, Chris

doi:10.1002/9780470035009.ch12

Cited by 10 publications

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“…Previous studies have clearly shown the importance of intrinsic membrane potassium and calcium currents for the auto-activity of RVLM sympathetic premotor neurons exposed to hypoxia in vitro (Sun & Reis, 1994a;Golanov & Reis, 1999;Wang et al 2001). Moreover, hypercapnia and hypoxia can activate intrinsic membrane conductances to induce tonic firing, which include oxygen-sensitive potassium (Archer et al 2006), calcium-dependent potassium (Kemp et al 2006) and TASK channels (Berg et al 2004). Note that both neurons and glia within hypoxic tissue normally leak potassium ions that can further boost membrane depolarization (Ballanyi, 2004), which can enhance pacemaking.…”

Section: Discussionmentioning

confidence: 98%

Intrinsic chemosensitivity of rostral ventrolateral medullary sympathetic premotor neurons in the in situ arterially perfused preparation of rats

Koganezawa

Paton

2014

Experimental Physiology

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New Findings r What is the central question of this study?Brain hypoperfusion is a key factor triggering hypertension through activation of cardiovascular sympathetic vasomotor nerves. However, mechanisms of detecting brain hypoperfusion remain unclear. We hypothesized that the sympathetic premotor neurons in the rostral ventrolateral medulla (RVLM) can sense asphyxia and cause sympathoexcitation. r What is the main finding and its importance?Functionally identified RVLM sympathetic premotor neurons were excited by hypoxia but less so by hypercapnia, before and after blockade of synaptic transmission. The RVLM sympathetic premotor neurons can act as an important oxygen sensor during brain hypoxia/hypoperfusion, which may be important in maintaining sympathetic nerve discharge to support blood pressure and hence maintain brain perfusion.Brainstem hypoperfusion is a major excitant of sympathetic activity triggering hypertension, but the exact mechanisms involved remain incompletely understood. A major source of excitatory drive to preganglionic sympathetic neurons originates from the ongoing activity of premotor neurons in the rostral ventrolateral medulla (RVLM sympathetic premotor neurons). The chemosensitivity profile of physiologically characterized RVLM sympathetic premotor neurons during hypoxia and hypercapnia remains unclear. We examined whether physiologically characterized RVLM sympathetic premotor neurons can sense brainstem ischaemia intrinsically. We addressed this issue in a unique in situ arterially perfused preparation before and after a complete blockade of fast excitatory and inhibitory synaptic transmission. During hypercapnic hypoxia, respiratory modulation of RVLM sympathetic premotor neurons was lost, but tonic firing of most RVLM sympathetic premotor neurons was elevated. After blockade of fast excitatory and inhibitory synaptic transmission, RVLM sympathetic premotor neurons continued to fire and exhibited an excitatory firing response to hypoxia but not hypercapnia. This study suggests that RVLM sympathetic premotor neurons can sustain high levels of neuronal discharge when oxygen is scarce. The intrinsic ability of RVLM sympathetic premotor neurons to maintain responsivity to brainstem hypoxia is an important mechanism ensuring adequate arterial pressure, essential for maintaining cerebral perfusion in the face of depressed ventilation and/or high cerebral vascular resistance.

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Section: Discussionmentioning

confidence: 98%

Intrinsic chemosensitivity of rostral ventrolateral medullary sympathetic premotor neurons in the in situ arterially perfused preparation of rats

Koganezawa

Paton

2014

Experimental Physiology

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“…Cornfield et al (66,67) have also provided compelling evidence that the large-conductance Ca 2ϩ -activated K ϩ channels or maxi K ϩ channels are developmentally regulated and distinctively distributed (in terms of activity and expression level) in different PASMC. Hypoxia regulates maxi K ϩ channel activity via an adjacent heme oxygenase (2,36,37,82). What types of K ϩ channel subunits contribute to whole-cell K ϩ currents seem to be very important to the cells, because it determines, at least, the sensitivity of I K(V) to hypoxia.…”

Section: Discussionmentioning

confidence: 99%

Heterogeneity of hypoxia-mediated decrease inI_K(V)and increase in [Ca²⁺]_cytin pulmonary artery smooth muscle cells

Platoshyn¹,

Yu²,

Ko³

et al. 2007

American Journal of Physiology-Lung Cellular and Molecular Phys

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Hypoxic pulmonary vasoconstriction is caused by a rise in cytosolic Ca(2+) ([Ca(2+)](cyt)) in pulmonary artery smooth muscle cells (PASMC) via multiple mechanisms. PASMC consist of heterogeneous phenotypes defined by contractility, proliferation, and apoptosis as well as by differences in expression and function of various genes. In rat PASMC, hypoxia-mediated decrease in voltage-gated K(+) (Kv) currents (I(K(V))) and increase in [Ca(2+)](cyt) were not uniformly distributed in all PASMC tested. Acute hypoxia decreased I(K(V)) and increased [Ca(2+)](cyt) in approximately 46% and approximately 53% of PASMC, respectively. Using combined techniques of single-cell RT-PCR and patch clamp, we show here that mRNA expression level of Kv1.5 in hypoxia-sensitive PASMC (in which hypoxia reduced I(K(V))) was much greater than in hypoxia-insensitive cells (in which hypoxia negligibly affected I(K(V))). These results demonstrate that 1) different PASMC express different Kv channel alpha- and beta-subunits, and 2) the sensitivity of a PASMC to acute hypoxia partially depends on the expression level of Kv1.5 channels; hypoxia reduces whole-cell I(K(V)) only in PASMC that express high level of Kv1.5. In addition, the acute hypoxia-mediated changes in [Ca(2+)](cyt) also vary in different PASMC. Hypoxia increases [Ca(2+)](cyt) only in 34% of cells tested, and the different sensitivity of [Ca(2+)](cyt) to hypoxia was not related to the resting [Ca(2+)](cyt). An intrinsic mechanism within each individual cell may be involved in the heterogeneity of hypoxia-mediated effect on [Ca(2+)](cyt) in PASMC. These data suggest that the heterogeneity of PASMC may partially be related to different expression levels and functional sensitivity of Kv channels to hypoxia and to differences in intrinsic mechanisms involved in regulating [Ca(2+)](cyt).

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“…Secondly, it is possible that it is the influence of the BK channel on the membrane potential that is critical, as it is in vascular tissue (Ledoux et al, 2006 ). In many cell types, BK channels also function as O 2 sensors (Kemp et al, 2006 ), and hypoxia is a condition important to the function of chondrocytes (Pfander and Gelse, 2007 ; Srinivas et al, 2009 ). BK channels could therefore be involved in coupling O 2 tension and mechanical pressure to membrane potential.…”

Section: Discussionmentioning

confidence: 99%

Characterization of a stretch‐activated potassium channel in chondrocytes

Mobasheri

Lewis

Maxwell

et al. 2010

Journal Cellular Physiology

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Chondrocytes possess the capacity to transduce load-induced mechanical stimuli into electrochemical signals. The aim of this study was to functionally characterize an ion channel activated in response to membrane stretch in isolated primary equine chondrocytes. We used patch-clamp electrophysiology to functionally characterize this channel and immunohistochemistry to examine its distribution in articular cartilage. In cell-attached patch experiments, the application of negative pressures to the patch pipette (in the range of 20–200 mmHg) activated ion channel currents in six of seven patches. The mean activated current was 45.9 ± 1.1 pA (n = 4) at a membrane potential of 33 mV (cell surface area approximately 240 µm2). The mean slope conductance of the principal single channels resolved within the total stretch-activated current was 118 ± 19 pS (n = 6), and reversed near the theoretical potassium equilibrium potential, EK+, suggesting it was a high-conductance potassium channel. Activation of these high-conductance potassium channels was inhibited by extracellular TEA (Kd approx. 900 µM) and iberiotoxin (Kd approx. 40 nM). This suggests that the current was largely carried by BK-like potassium (MaxiK) channels. To further characterize these BK-like channels, we used inside-out patches of chondrocyte membrane: we found these channels to be activated by elevation in bath calcium concentration. Immunohistochemical staining of equine cartilage samples with polyclonal antibodies to the α1- and β1-subunits of the BK channel revealed positive immunoreactivity for both subunits in superficial zone chondrocytes. These experiments support the hypothesis that functional BK channels are present in chondrocytes and may be involved in mechanotransduction and chemotransduction.

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Functional Proteomics of BK Potassium Channels: Defining the Acute Oxygen Sensor

Cited by 10 publications

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Intrinsic chemosensitivity of rostral ventrolateral medullary sympathetic premotor neurons in the in situ arterially perfused preparation of rats

Intrinsic chemosensitivity of rostral ventrolateral medullary sympathetic premotor neurons in the in situ arterially perfused preparation of rats

Heterogeneity of hypoxia-mediated decrease inI_K(V)and increase in [Ca²⁺]_cytin pulmonary artery smooth muscle cells

Characterization of a stretch‐activated potassium channel in chondrocytes

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Functional Proteomics of BK Potassium Channels: Defining the Acute Oxygen Sensor

Cited by 10 publications

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Intrinsic chemosensitivity of rostral ventrolateral medullary sympathetic premotor neurons in the in situ arterially perfused preparation of rats

Intrinsic chemosensitivity of rostral ventrolateral medullary sympathetic premotor neurons in the in situ arterially perfused preparation of rats

Heterogeneity of hypoxia-mediated decrease inIK(V)and increase in [Ca2+]cytin pulmonary artery smooth muscle cells

Characterization of a stretch‐activated potassium channel in chondrocytes

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Heterogeneity of hypoxia-mediated decrease inI_K(V)and increase in [Ca²⁺]_cytin pulmonary artery smooth muscle cells