K+ channels in O2 sensing and postnatal development of carotid body glomus cell response to hypoxia

Abstract

The sensitivity of carotid body chemoreceptors to hypoxia is low just after birth and increases over the first few weeks of the postnatal period. At present, it is believed that the hypoxia-induced excitation of carotid body glomus cells begins with the inhibition of the outward K+ current via one or more O2 sensors. Although the nature of the O2 sensors and their signals that inhibit the K+ current are not well defined, studies suggest that the postnatal maturation of the glomus cell response to hypoxia is largely due to the increased sensitivity of K+ channels to hypoxia. As KV, BK and TASK channels that are O2-sensitive contribute to the K+ current, it is important to identify the O2 sensor and the signaling molecule for each of these K+ channels. Various O2 sensors (mitochondrial hemeprotein, hemeoxygenase-2, NADPH oxidase) and associated signals have been proposed to mediate the inhibition of K+ channels by hypoxia. Studies suggest that a mitochondrial hemeprotein is likely to serve as an O2 sensor for K+ channels, particularly for TASK, and that multiple signals may be involved. Thus, changes in the sensitivity of the mitochondrial O2 sensor to hypoxia, the sensitivity of K+ channels to signals generated by mitochondria, and/or the expression levels of K+ channels are likely to account for the postnatal maturation of O2 sensing by glomus cells.

Carotid chemoreceptor “resetting” revisited

“…Indeed, we found that hypoxic inhibition of TASK activity was least at P0-1 and increased significantly with postnatal age, mainly between P6-7 and P16-18, supporting the hypothesis that changes in TASK O 2 sensitivity underlie, at least in part, the postnatal increase in glomus cell O 2 sensitivity (Fig. 3G, H) (Kim et al, 2011) (See Kim, 2012 for review).…”

“…Interestingly, using free fatty acids, membrane stretch and acid to activate TREK channels (which are normally inactive in cell-attached patches) we found TREK activation in about 30% of patches from P0-1 rats compared with 0% at P16-18 (Kim, 2012). Thus, TREK channels are functionally expressed by CB glomus cells and this expression appears to decline after birth.…”

“…KV channels may not be active at resting membrane potential, and therefore would be unlikely to initiate depolarization. However, their inhibition by hypoxia could enhance the magnitude and/or duration of depolarization (Kim, 2012). The precise role of KV channels in CB functional maturation will require further study, ideally in rat, rabbit and mouse.…”

“…Never-the-less, because TREK is normally not active unless stimulated by mechanical stretch, etc., TREK channels are unlikely to play a role in functional glomus cell O 2 response maturation. TREK, KV, K ATP , K ir and other K + channels in CB development have recently been reviewed in detail and will not be further discussed here (Kim, 2012). …”

Effects of modulators of AMP-activated protein kinase on TASK-1/3 and intracellular Ca2+ concentration in rat carotid body glomus cells

“…It may be that different O 2 sensors and signals are involved in the inhibition of specific K + channels, but this remains to be determined. The inhibition of mitochondrial oxidative phosphorylation is probably responsible for the hypoxia-induced reduction of TASK, as mitochondrial inhibitors and uncouplers reversibly inhibit these two-pore domain background K + channels (Buckler, 2007, 2012; Kim, 2013). …”