Molecular underpinnings of ventral surface chemoreceptor function: focus on KCNQ channels

Abstract

Central chemoreception is the mechanism by which CO₂/H(+) -sensitive neurons (i.e. chemoreceptors) regulate breathing in response to changes in tissue CO₂/H(+) . Neurons in the retrotrapezoid nucleus (RTN) directly regulate breathing in response to changes in tissue CO₂/H(+) and function as a key locus of respiratory control by integrating information from several respiratory centres, including the medullary raphe. Therefore, chemosensitive RTN neurons appear to be critically important for maintaining breathing, thus understanding molecular mechanisms that regulate RTN chemoreceptor function may identify therapeutic targets for the treatment of respiratory control disorders. We have recently shown that KCNQ (Kv7) channels in the RTN are essential determinants of spontaneous activity ex vivo, and downstream effectors for serotonergic modulation of breathing. Considering that loss of function mutations in KCNQ channels can cause certain types of epilepsy including those associated with sudden unexplained death in epilepsy (SUDEP), we propose that dysfunctions of KCNQ channels may be one cause for epilepsy and respiratory problems associated with SUDEP. In this review, we will summarize the role of KCNQ channels in the regulation of RTN chemoreceptor function, and suggest that these channels represent useful therapeutic targets for the treatment of respiratory control disorders.

Figure 1

Working model of molecular mechanisms that regulate the basal activity of chemosensitive RTN neurons A, under control conditions (5% CO₂, pH 7.3) loss of functional KCNQ (Hawryluk et al. 2012), THIK-1 (Lazarenko et al. 2010), TASK-2 (Wang et al. a) or HCN (Hawkins et al. 2014) channels results in increased chemoreceptor activity, thus indicating these channels contribute to basal activity of RTN chemoreceptors. Note that THIK-1 channels are voltage independent and are not known to be modulated by physiological stimuli, so we suspect they provide a tonic inhibitory current under all conditions. Note also that HCN channels are not active at depolarized potentials and are not likely to contribute to stimulated activity. B, CO₂/H⁺-mediated inhibition of TASK-2 channels increases chemoreceptor activity, while at the same time KCNQ channels become more active with depolarization (depicted as a thicker arrow) thus helping to prevent overactivation. C, blocking KCNQ channels results in a left (excitatory) shift in the firing rate response of RTN chemoreceptors to CO₂/H⁺ and reveals a role of SK channels as secondary brakes on chemoreceptor activity, i.e. SK channels contribute to the activity of these cells only in the absence of functional KCNQ channels. D, blockade of both KCNQ and SK channels results in enhanced neural responsiveness to CO₂/H⁺. These results suggest that several channels contribute to the basal activity of RTN chemoreceptors; chief among these are KCNQ and TASK-2.

Figure 2

KCNQ channels mediate the effects of serotonin on RTN chemoreceptors and breathing in sedated and awake rats A, activity of neurons in brain slices from rat pups (7–12 days postnatal) were measured in the cell-attached configuration (firing-rate histograms were generated by integrating the number of action potentials measured over time), RTN chemoreceptors were identified based on their characteristic firing rate response to hypercapnia. This firing rate trace (left) and summary data (right, n = 7) shows the response of RTN chemoreceptors to serotonin (5 μm) under control conditions and during KCNQ channel blockade with XE991 (10 μm). Note that XE991 increased chemoreceptor activity, as expected for inhibition of a sub-threshold K⁺ conductance. In the presence of XE991 (with baseline adjusted to near control level by DC current injection) the firing response to serotonin was reduced by ∼50%. // marks a 10 min time break and arrow designates DC current injection. B, trace of integrated phrenic nerve discharge (∫PND) and summary data (n = 5) show that unilateral injection of XE991 (50 μm) into the RTN of an anaesthetized rat decreased excitatory effects of serotonin (1 mm) on PND amplitude. Note that bilateral RTN injections of XE991 are required to elicit measurable effects on breathing. C, plethysmography trace of inspiratory activity and summary data plotted as minute ventilation (n = 6) show that XE991 (50 μm) decreased the ventilatory response of awake rats to RTN injections of serotonin (1 mm). *Significant difference between control and XE991. Redrawn with permission from Hawryluk et al. (2012).