Model of 02 Sensing in Neonatal AMC

We propose the following model for the 02 signaling pathway in AMC (Fig. 5). During hypoxia, 02 availability is decreased and ROS generation at a critical site of the proximal ETC is reduced. The key ROS may be H202, which is generated in the mitochondria by the dismutation of 02", is freely diffusible, and can be long-lived depending on catalase levels in the cell. The combined inhibition of BK, SK, and Kv channels leads to or enhances membrane depolarization and action potential broadening, increasing Ca2+ influxthrough nifedipine-sensitive L-type Ca2+ channels and CA secretion. Although controversial, it appears that the ability of AMC to directly respond to hypoxia disappears along a time course similar to the maturation of sympathetic innervation to the adrenal gland.

Figure 5. A working model of the 02-sensing mechanism of neonatal AMC. Hypoxia is detected by the electron transport chain (ETC), a component of the inner mitochondrial membrane (IMM), reducing the production of superoxide radical (02") from the ETC. 02'~ is rapidly dismutated to H202 by the mitochondrial enzyme superoxide dismutase (SOD) and crosses the outer mitochondrial membrane (OMM). The overall decrease in cytoplasmic H202 modulates plasma membrane ion channels. It is proposed that SK channels are inhibited and KAXP channels activated, resulting in a receptor potential. KAXP channels appear to limit the magnitude of the receptor potential. Additionally, in spontaneously active AMC, H202 is hypothesized to inhibit large-conductance Ca2+-activated (BK) and delayed-rectifier (Kvl .2/1.5) channels, thereby broadening the action potentials. The combined receptor potential and modulation of the action potential waveform opens L-type Ca2+ channels, causing Ca2+ influx and catecholamine exocytosis.

Figure 5. A working model of the 02-sensing mechanism of neonatal AMC. Hypoxia is detected by the electron transport chain (ETC), a component of the inner mitochondrial membrane (IMM), reducing the production of superoxide radical (02") from the ETC. 02'~ is rapidly dismutated to H202 by the mitochondrial enzyme superoxide dismutase (SOD) and crosses the outer mitochondrial membrane (OMM). The overall decrease in cytoplasmic H202 modulates plasma membrane ion channels. It is proposed that SK channels are inhibited and KAXP channels activated, resulting in a receptor potential. KAXP channels appear to limit the magnitude of the receptor potential. Additionally, in spontaneously active AMC, H202 is hypothesized to inhibit large-conductance Ca2+-activated (BK) and delayed-rectifier (Kvl .2/1.5) channels, thereby broadening the action potentials. The combined receptor potential and modulation of the action potential waveform opens L-type Ca2+ channels, causing Ca2+ influx and catecholamine exocytosis.

Clearly, this model will have to be tested more rigorously using excised patches from AMC to determine modulation of the channels by putative second messengers (e.g., H202) and with knockout models that lack key ETC proteins. The fact that the 02-sensitivity of these cells appears to be intimately associated with innervation (25, 33) means that this naturally-occurring developmental change in phenotype may be used as a powerful tool for elucidating the molecular identity of the sensor. Future work should focus on determining how the change in phenotype develops and what are the cellular and molecular mechanisms that contribute to it.

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