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Increase in cytosolic Ca 2+ produced by hypoxia and other depolarizing stimuli activates a non‐selective cation channel in chemoreceptor cells of rat carotid body
Author(s) -
Kang Dawon,
Wang Jiaju,
Hogan James O.,
Vennekens Rudi,
Freichel Marc,
White Carl,
Kim Donghee
Publication year - 2014
Publication title -
the journal of physiology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.802
H-Index - 240
eISSN - 1469-7793
pISSN - 0022-3751
DOI - 10.1113/jphysiol.2013.266957
Subject(s) - carotid body , depolarization , glomus cell , biophysics , extracellular , chemistry , intracellular , hypoxia (environmental) , membrane potential , chemoreceptor , medicine , endocrinology , electrophysiology , biochemistry , biology , receptor , oxygen , organic chemistry
Key points Hypoxia is thought to depolarize glomus cells by inhibiting the outward K + current, which sets in motion a cascade of ionic events that lead to transmitter secretion, increased afferent carotid sinus nerve activity and increased ventilation. Our study of Na + ‐permeable channels in glomus cells has revealed that hypoxia not only inhibits TASK background K + channels but also indirectly activates a non‐selective cation channel with a single channel conductance of 20 pS. Under physiological conditions, the reversal potential of the cation channel is ∼ –28 mV, indicating that Na + influx is also involved in hypoxia‐induced excitation of glomus cells. Activation of the 20 pS cation channel is present when the O 2 content is 5% or less, indicating that Na + influx occurs during moderate to severe hypoxia (<5% O 2 ), but not mild hypoxia (>5% O 2 ). The 20 pS cation channel is directly activated by a rise in intracellular Ca 2+ . Thus, factors that elevate intracellular Ca 2+ such as hypoxia, extracellular acidosis and high external KCl all activate the cation channel. A feed‐forward mechanism may be present in which an initial depolarization‐induced rise in intracellular Ca 2+ opens the Na + ‐permeable cation channel, and the Na + influx causes additional depolarization and influx of Ca 2+ into glomus cells.Abstract The current model of O 2 sensing by carotid body chemoreceptor (glomus) cells is that hypoxia inhibits the outward K + current and causes cell depolarization, Ca 2+ influx via voltage‐dependent Ca 2+ channels and a rise in intracellular [Ca 2+ ] ([Ca 2+ ] i ). Here we show that hypoxia (<5% O 2 ), in addition to inhibiting the two‐pore domain K + channels TASK‐1/3 (TASK), indirectly activates an ∼20 pS channel in isolated glomus cells. The 20 pS channel was permeable to K + , Na + and Cs + but not to Cl − or Ca 2+ . The 20 pS channel was not sensitive to voltage. Inhibition of TASK by external acid, depolarization of glomus cells with high external KCl (20 m m ) or opening of the Ca 2+ channel with FPL64176 activated the 20 pS channel when 1 m m Ca 2+ was present in the external solution. Ca 2+ (10 μ m ) applied to the cytosolic side of inside‐out patches activated the 20 pS channel. The threshold [Ca 2+ ] i for activation of the 20 pS channel in cell‐attached patches was ∼200 n m . The reversal potential of the 20 pS channel was estimated to be −28 mV. Our results reveal a sequential mechanism in which hypoxia (<5% O 2 ) first inhibits the K + conductance and then activates a Na + ‐permeable, non‐selective cation channel via depolarization‐induced rise in [Ca 2+ ] i . Our results suggest that inhibition of K + efflux and stimulation of Na + influx both contribute to the depolarization of glomus cells during moderate to severe hypoxia.