Sensitive K Channels and Stimulussecretion Coupling in Glomus Cells

The typical macroscopic ionic currents recorded from dispersed rabbit carotid body cells maintained in normoxic conditions (Po2« 150 mmHg) are illustrated in Figure 1A. On depolarization the cells generate an inward current, mainly mediated by Ca2+ channels, followed by an outward K+ current. The large inward tail current at the end of the pulse reflects the influx of Ca2+ through the channels and their closing time course. The outward K+ current is selectively and reversibly reduced in amplitude upon exposure to the same external solution but with aPO2»30mmHg.Figure IB shows single-channel recordings obtained from an excised membrane patch containing one 02-sensitive ion channel whose peak open probability was reduced to almost 50% on switching from normoxia to hypoxia (11, 12).

Figure 1. Major 02 dependent electrophysiological properties of glomus cells. A: Macroscopic inward and outward currents of glomus cells and reversible inhibition of the outward current by hypoxia (Po2 » 20 mmHg). Control and recovery traces in normoxia (Po2 = 150 mmHg) are shown superimposed. In this experiment TTX was added to block the Na+ conductance. B: Singlechannel recordings from an excised membrane patch containing at most one open 02-sensitive K+ channel. Depolarizing pulses were applied from -80 to +20 mV. Ensemble averages indicating the single-channel open probability in normoxia and hypoxia are from 15 and 22 successive recordings, respectively (modified from Refs. 11,26).

Figure 1. Major 02 dependent electrophysiological properties of glomus cells. A: Macroscopic inward and outward currents of glomus cells and reversible inhibition of the outward current by hypoxia (Po2 » 20 mmHg). Control and recovery traces in normoxia (Po2 = 150 mmHg) are shown superimposed. In this experiment TTX was added to block the Na+ conductance. B: Singlechannel recordings from an excised membrane patch containing at most one open 02-sensitive K+ channel. Depolarizing pulses were applied from -80 to +20 mV. Ensemble averages indicating the single-channel open probability in normoxia and hypoxia are from 15 and 22 successive recordings, respectively (modified from Refs. 11,26).

Reduction of K+ conductance in hypoxia is expected to produce an increase in glomus cell excitability leading to Ca2+ influx and secretion. This has been shown to occur in dispersed glomus cells loaded with the Ca2+ indicator Fura2-AM in which single cell secretion was monitored by amperometry (5, 26, 39). Note in Figure 2A that, upon exposure to hypoxia, the increase in cytosolic [Ca2+] is paralleled by the appearance of spike-like quantal events corresponding to the release of dopamine (the most abundant catecholamine in glomus cells) from individual vesicles. The current model ofglomus cell activation by hypoxia is shown diagrammatically in Figure 2B. Sensing of low P02 is done through inhibition of the K+ conductance (GK, 1), which leads to increase of action potential firing frequency (2), Ca2+ influx (3) and secretion (4) ofthe transmitters that activate the afferent fibers of the sinus nerve (5). However, the K+ channel type modulated by Po2 appears to change among the various species (22), and inhibition (26) and potentiation (37) of the Ca2+ current by hypoxia in rabbit glomus cells have also been reported.

Figure 2. Secretory response of single glomus cells to low Po2. A: Parallel changes of Po2, [Ca2+]j, and dopamine secretion in a glomus cell in response to hypoxia. Cytogolic [Ca2+] was measured by microfluorimetry with Fura-2. Dopamine release was monitored by amperometry with a 6 (im polarized carbon fiber electrode and quantal secretory events appeared as spike like activity representing the fusion of individual secretory vesicles. B: Schematic diagram of the major steps in a model of sensory transduction involving 02-sensitive ion channels in glomus cells. 1) 02 sensing by K+ channels. 2) Hypoxic reduction of the Kf conductance (GK) leads to an increase in the action potential frequency and Cai+ influx. 3) Rise of cytosolic [Ca2+], 4) Transmitter release. 5) Activation of the afferent fibers of the sinus nerve (Modified from Refs. 19,26,39).

Figure 2. Secretory response of single glomus cells to low Po2. A: Parallel changes of Po2, [Ca2+]j, and dopamine secretion in a glomus cell in response to hypoxia. Cytogolic [Ca2+] was measured by microfluorimetry with Fura-2. Dopamine release was monitored by amperometry with a 6 (im polarized carbon fiber electrode and quantal secretory events appeared as spike like activity representing the fusion of individual secretory vesicles. B: Schematic diagram of the major steps in a model of sensory transduction involving 02-sensitive ion channels in glomus cells. 1) 02 sensing by K+ channels. 2) Hypoxic reduction of the Kf conductance (GK) leads to an increase in the action potential frequency and Cai+ influx. 3) Rise of cytosolic [Ca2+], 4) Transmitter release. 5) Activation of the afferent fibers of the sinus nerve (Modified from Refs. 19,26,39).

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