All for one – O2‐sensitive K+ channels that mediate carotid body activation

The hypoxic ventilatory response is a homeostatic reflex essential for the survival of mammals in environmental or pathological conditions that present with hypoxaemia (low in the blood). Changes in blood are detected by neural crest-derived and O2-sensitive glomus cells (also named type I or chief cells) in the carotid body (CB), the most important arterial chemoreceptor organ. In response to hypoxia, CB glomus cells release transmitters to activate afferent sensory fibres that synapse on neurons in the brainstem respiratory centre (for a recent review see López-Barneo et al. 2016). The notion that hypoxia (low ) causes inhibition of membrane K+ conductance in glomus cells to elicit depolarization, voltage-gated Ca2+ entry, and neurotransmitter release is widely accepted; however, the relevance of the several classes of K+ channels expressed in glomus cells for the initiation or maintenance of the hypoxic response is not well understood. In this issue of The Journal of Physiology, Wang & Kim (2018) report an elegant and detailed study suggesting differential roles of background and voltage-dependent K+ channels in hypoxic CB activation. Wang & Kim (2018) measured cytosolic [Ca2+] ([Ca2+]i) in enzymatically dispersed juvenile rat glomus cells to study the effects of K+-channel blockers alone or in combination with variable levels of hypoxia and membrane depolarization (elicited by increasing [K+] in the external solution). They used high concentrations of iberiotoxin (Ibtx, a specific blocker of Ca2+- and voltage-dependent maxi-K+ channels) or tetraethylammonium plus 4-aminopyridine (TEA + 4AP), a pharmacological combination that blocks most voltage-gated (Kv) K+ channels. An initial observation in Wang and Kim's work is that, in contrast with hypoxia, which induced a dose-dependent increase in [Ca2+]i in the cells studied, Ibtx or TEA + 4AP failed to produce any change in [Ca2+]i. However, these drugs, in particular TEA + 4AP, elicited an increase in [Ca2+]i when cells were previously depolarized by >15 mm K+. In resting cells, TEA + 4AP strongly potentiated the hypoxia-induced rise in [Ca2+]i, although Ibtx had little effect. In agreement with these observations, a marked potentiation of the hypoxia-induced rise in [Ca2+]i was also elicited by guangxitoxin, a selective blocker of Kv2 channels which seem to mediate more than half of the voltage-dependent K+ current in rat glomus cells. In a separate set of experiments, Wang & Kim (2018) also showed that in cell-attached or excised membrane patches, maxi-K+ channel activity is not affected by hypoxia. Based on these data, the authors concluded that maxi-K+ and Kv channels do not significantly contribute to the hypoxia-induced depolarization in rat glomus cells. They proposed that the main role of Kv channels, and less significantly maxi-K+ channels, is to limit the hypoxia response by opposing membrane depolarization and the opening of voltage-gated Ca2+ channels. The proposal that background K+ channels mediate the predominant ionic conductance in glomus cells and, therefore, are the main channels responsible for setting the cell's resting potential has solid foundations. However, the contribution of maxi-K+ or Kv channels to glomus cell physiological parameters must not be underestimated as in the CB in situ these cells may be electrically coupled and subjected to auto- and paracrine interactions as well as modulation by efferent fibres, which could bring the cell's resting potential or [Ca2+]i to values at which a fraction of Kv or maxi-K+ channels are open. Indeed, Wang & Kim (2018) have nicely shown that when their dispersed glomus cells are slightly depolarized with high external K+, the addition of 4-AP + TEA or even Ibtx can elicit appreciable increases in [Ca2+]i. In addition, it has been shown that Ibtx and TEA can induce secretion from resting glomus cells in rat or mouse CB slices (see Ortega-Sáenz et al. (2010) and references therein). Wang and Kim's data strongly support the view that inhibition of background K+ channels initiates the depolarizing response to hypoxia in rat glomus cells, a concept that could be also applicable to CB cells in other mammalian species (see Buckler, 2015). In Wang and Kim's scheme, the role played by voltage-gated channels is to merely function as a feedback mechanism to prevent further membrane depolarization and thus limit the hypoxic activation of cells. However, as it is well established that Kv channels are also modulated by (see López-Barneo et al. (2016) and references therein), a more comprehensive view, therefore, is that by reducing their open probability, low counteracts Kv channel activation by membrane voltage and facilitates the cell's hypoxic response. In recent years it has become evident that the acute hypoxia-signalling pathway is mediated by promiscuous signals (reactive oxygen species among others) that can redundantly modulate several classes of ‘O2-sensitive’ ion channels (see López-Barneo et al. 2016). In support of this notion, responsiveness to hypoxia in CB slices is fully maintained in Task1/Task3 double knockout mice (Ortega-Sáenz et al. 2010), despite these genes encoding the main background K+ channel subunits inhibited by hypoxia in mouse and rat glomus cells (see Buckler, 2015; Wang & Kim, 2018). Enzymatically dispersed Task1/Task3-null glomus cells have a relatively depolarized resting potential with respect to controls, which could determine the participation of Kv or other ion channels in the hypoxic response (Ortega-Sáenz et al. 2010; Kang et al. 2014). On translational grounds, the robust potentiation of the glomus cell chemosensory response by K+ channel blockers, clearly illustrated in Wang and Kim's report, reminds us of the medical need for safe and efficacious CB stimulants to fight against inhibition of respiration. Research on selective blockers of K+ channels in human CB cells could give rise to drugs of potential use in anaesthesia and respiratory medicine. Most notably, these drugs could become first-line weapons to combat the expanding epidemic of fatal opioid-induced respiratory depression. The author declares no competing interests. Funding to the author's laboratory was provided by the Spanish Ministry of Economy and Innovation (SAF2016-74990-R) and the European Research Council (ERC Advanced Grant PRJ201502629).