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. 2015 Feb 19;593(Pt 5):1075–1081. doi: 10.1113/jphysiol.2014.286500

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

Daniel K Mulkey 1,✉, Virginia E Hawkins 1, Joanna M Hawryluk 1, Ana C Takakura 2, Thiago S Moreira 3, Anastasios V Tzingounis 1
PMCID: PMC4358672  PMID: 25603782

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.

Chemosensitive neurons in the retrotrapezoid nucleus

Central chemoreception is the mechanism by which the brain regulates breathing in response to changes in tissue CO2/H+ (Nattie & Li, 2012; Guyenet, 2014). A brainstem region known as the retrotrapezoid nucleus (RTN) is an important site of central chemoreception. Neurons (Mulkey et al. 2004) and astrocytes (Gourine et al. 2010) in this region sense changes in CO2/H+ to produce an integrated CO2/H+-dependent drive to breathe. Here we focus on mechanisms that regulate the activity of chemosensitive RTN neurons. These neurons are known to express the transcription factor Phox2b and are intrinsically CO2/H+ sensitive in vivo (Mulkey et al. 2004) and in vitro (Onimaru et al. 2012; Wang et al. 2013b); they are glutamatergic and project to all segments of the respiratory network to regulate both inspiratory and expiratory activity (Guyenet, 2014). Furthermore, although the pre-Bötzinger complex is essential for respiratory rhythm generation (Feldman & Del Negro, 2006), a subset of RTN-Phox2b neurons may also comprise the respiratory parafacial group (pFRG) and contribute to respiratory rhythm generation (Onimaru et al. 2008; Thoby-Brisson et al. 2009; Pagliardini et al. 2011; Feldman et al. 2013). The contributions of RTN chemoreceptors to breathing in adult animals has been convincingly demonstrated using optogenetic approaches. For example, channelrhodopsin-mediated activation of RTN-Phox2b neurons has been shown to increase inspiratory and expiratory activity in sedated and conscious animals (Abbott et al. 2009, 2011; Kanbar et al. 2010; Pagliardini et al. 2011), whereas allatostatin-mediated inhibition of RTN-Phox2b neurons decreased basal respiratory activity in sedated but not conscious rats, and decreased CO2-evoked expiratory activity in carotid-denervated rats as well as the inspiratory response to CO2 in denervated anaesthetized rats and conscious rats with peripheral chemoreceptors intact (Marina et al. 2010). Disruption of RTN-Phox2b neurons also results in the loss of respiratory chemosensitivity (Dubreuil et al. 2008; Takakura et al. 2014); however, despite the loss of RTN-Phox2b neurons animals survive to adulthood presumably due to compensation by peripheral chemoreceptors (Ramanantsoa et al. 2011) or other brainstem chemoreceptors like those in the raphe (Hodges et al. 2009; Richerson, 2004), nucleus of the tractus solitarius (Dean & Putnam, 2010) and locus coeruleus (Gargaglioni et al. 2010). These findings indicate that RTN-Phox2b neuronal activity has a powerful influence on all aspects of breathing. Therefore, understanding mechanisms that regulate the activity of these cells will provide a molecular basis for how the brain controls breathing and may lead to new therapeutic avenues for the treatment of respiratory disorders. Recent evidence identifies KCNQ channels as key determinants of RTN chemoreceptor function. Therefore, in this short review we will summarize evidence implicating KCNQ channels in the control of breathing, and suggest that these channels are potential therapeutic targets for the treatment of respiratory dysfunction.

KCNQ channels regulate the activity of RTN chemoreceptors

The KCNQ family of K+ channels (KCNQ1–5) are essential regulators of neuronal excitability (Jentsch, 2000; Tzingounis & Nicoll, 2008); neurons predominantly express KCNQ2–5 (Jentsch, 2000), although recent evidence also suggests that KCNQ1 channels are expressed in the brain (Goldman et al. 2009). KCNQ channels, namely KCNQ2 and KCNQ3, are thought to be the molecular substrate of the M-current (Wang et al. 1998; Shapiro et al. 2000), a sub-threshold conductance that contributes to resting membrane potential and stimulated activity (Battefeld et al. 2014). Additionally, KCNQ channels control neural activity by contributing to the medium afterhyperpolarization (mAHP) following a burst of action potentials, thus potentially slowing repetitive firing (Soh et al. 2014). The importance of KCNQ channels to neural function is underscored by evidence that drugs which stimulate KCNQ channels (retigabine) are used clinically to treat epilepsy (Ciliberto et al. 2012) and drugs that inhibit KCNQ channels (linopirdine or its derivative XE991) may enhance cognitive function (Surti & Jan, 2005). Insight into the function of individual KCNQ subunits has arisen from studies of genetically manipulated mice. In contrast to KCNQ3−/− and KCNQ5 dominant-negative mice, KCNQ2 knockout mice do not survive past 24 h due to respiratory failure (Watanabe et al. 2000; Otto et al. 2006; Tzingounis & Nicoll, 2008; Tzingounis et al. 2010), suggesting that KCNQ2 channels might play a vital role in the control of breathing. In addition, patients with Kcnq2 encephalopathy reportedly exhibit apnoea and in some cases die from sudden unexplained death in epilepsy (SUDEP) (Weckhuysen et al. 2013).

Consistent with a role of KCNQ channels in the control of breathing, we recently discovered that KCNQ channels influence the excitability of RTN chemoreceptors. For example, cell-attached recordings of membrane potential showed that pharmacological activation of KCNQ channels with retigabine inhibited tonic activity of chemosensitive RTN neurons with an IC50 of 0.6 μm (Hawryluk et al. 2012), which is most similar to the retigabine sensitivity of KCNQ2 (IC50 = 2.5 μm) and KCNQ3 channels (IC50 = 0.6 μm) (Gunthorpe et al. 2012). Conversely, the selective KCNQ channel blocker XE991 increased the activity of RTN chemoreceptors and caused a left (excitatory) shift in the firing rate response to CO2/H+ (Hawryluk et al. 2012). Further, whole-cell recordings of RTN chemoreceptor membrane potential responses to depolarizing and hyperpolarizing current steps showed that XE991 caused a modest increase in input resistance and increased the firing response to depolarizing current injections (Hawkins et al. 2014). These results indicate that KCNQ channels contribute to the resting and stimulated activity of RTN chemoreceptors in the brain slice preparation. We also showed in vivo that bilateral RTN injections of XE991 stimulated breathing and lowered the CO2 threshold for phrenic nerve discharge in anaesthetized rats (Hawryluk et al. 2012). These results indicate that KCNQ channels regulate the excitability of RTN chemoreceptors and respiratory activity but do not contribute to the mechanism by which these cells sense CO2/H+. Interestingly, we also found that KCNQ channels contribute to the inhibitory effects produced by activation of hyperpolarization-activated cyclic nucleotide-gated (HCN) channels on the basal activity of RTN chemoreceptors (Hawkins et al. 2014). HCN channels generate a hyperpolarization-activated inward current that can increase neuronal excitability. However, HCN channel activity can also inhibit excitability by decreasing input resistance or indirectly by influencing the activity of other voltage-gated channels, including KCNQ channels. Consistent with this, we found that under resting conditions application of an HCN channel blocker (ZD7288 or Cs2+) stimulated the activity of RTN chemoreceptors in conjunction with increased input resistance; however, when KCNQ channels were blocked with XE991 the response to HCN channel blockers was significantly reduced (Hawkins et al. 2014). We also found that HCN channels do not contribute to stimulated chemoreceptor activity (Hawkins et al. 2014), as expected for a conductance that is inhibited by depolarization.

Chemosensitive RTN neurons have also been shown to express members of the KCNK family of voltage-independent K+ channels which also temper RTN chemoreceptor activity. For example, the volatile anaesthetic isoflurane stimulates the activity of RTN chemoreceptors, in part, by inhibition of THIK-1 (Tandem of pore domain Weakly Inward rectifying K+ channel (TWIK)-related halothane-inhibited K+; Two-pore domain potassium channels (K2p)13.1) channels (Lazarenko et al. 2010), thus indicating that THIK-1 channels are active at resting membrane potential and serves to limit chemoreceptor excitability. Recent evidence also identifies TASK-2 (TWIK-related acid-sensitive K+; K2p5.1) channels as a key component of CO2/H+ sensing by RTN chemoreceptors, for example, genetic ablation of TASK-2 increased basal activity of RTN-Phox2b neurons in vitro and diminished the ventilatory response to CO2/H+ in vivo (Wang et al. 2013a). This contribution of TASK-2 to RTN chemoreceptor function appears unique among H+-sensitive KCNK channels since the genetic deletion of TASK-1 and TASK-3 had no effect on RTN chemoreceptor function or the central chemoreflex (Mulkey et al. 2007b).

Based on the above evidence, we propose the following model for intrinsic excitability of RTN chemoreceptors that is summarized in Fig.1. Under resting conditions (interstitial pH = 7.3) KCNQ, THIK-1, and to some extent TASK-2 channels, are active and together help limit chemoreceptor activity. Under these conditions, HCN channel activity also limits chemoreceptor activity indirectly by increasing KCNQ channel conductance (Hawkins et al. 2014). There is no evidence that THIK-1 activity is modulated under normal physiological conditions so in Fig.1 we depict the contribution of THIK-1 as a constant outward current. Exposure to high CO2 will inhibit TASK-2 channels and result in membrane depolarization and increased firing rate. HCN channel activity will decrease at depolarized potentials; conversely, voltage-gated KCNQ channel conductance will increase with depolarization to limit the CO2/H+-stimulated activity. However, blocking KCNQ channels did not result in enhanced CO2/H+ sensitivity; therefore, we propose that other channels limit stimulated activity of RTN neurons. Considering that chemosensitive RTN neurons also express Ca2+-activated K+ channels (SK channels) that work in concert with KCNQ channels to regulate the amplitude of evoked mAHPs, and blockade of both KCNQ and SK channels resulted in enhanced neural responsiveness to CO2 (Hawryluk et al. 2012), we propose that SK channels provide a mechanism for scaling neuronal responsiveness to stimuli like CO2 when KCNQ channels are blocked.

Figure 1.

Figure 1

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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. 2013a) 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.

KCNQ channels are downstream targets of serotonin in chemosensitive RTN neurons

In addition to providing a CO2/H+-dependent drive to breathe, chemosensitive RTN neurons also serve as a point of convergence for other respiratory centres including serotonergic raphe neurons (Rosin et al. 2006; Mulkey et al. 2007a). Serotonin is a neurotransmitter that is essential for maintaining respiratory activity (Richter et al. 2003) and disruption of serotonergic signalling has been shown to decrease the respiratory chemoreflex (Richerson, 2004; Hodges et al. 2009; Ray et al. 2011) and is thought to contribute to respiratory failure associated with SUDEP (Richerson, 2013; Massey et al. 2014). The mechanism(s) by which serotonin modulates breathing are not well understood. For example, serotonin strongly activates inspiratory neurons in the pre-Bötzinger complex by inhibition of resting K+ conductance and activation of an inward current (Ptak et al. 2009); however, the identity of channels contributing to this response remains unknown. At the level of the RTN, evidence showed that the response of RTN chemoreceptors to serotonin could be blocked by ketanserin (Mulkey et al. 2007a), suggesting involvement of Gq-coupled 5-HT2 receptors. Consistent with known inhibitory effects of Gq signalling on KCNQ channels (Wang et al. 1998; Shapiro et al. 2000), we found that KCNQ channels, but not SK channels, are downstream effectors of serotonin modulation of RTN chemoreceptor activity (Hawryluk et al. 2012). For example, pharmacological blockade of KCNQ channels in the RTN blunted the firing rate response to serotonin ex vivo (Fig.2A) and reduced the effects of serotonin on respiratory output in both sedated (Fig.2B) and awake (Fig.2C) rats in vivo. Other raphe transmitters that are eventually co-released with serotonin (e.g. substance P and thyrotropin-releasing hormone) are also known to stimulate RTN chemoreceptors by Gq signalling but do not appear to converge on KCNQ or SK channels (Hawryluk et al. 2012), thus RTN chemoreceptors are able to respond to multiple raphe transmitters simultaneously.

Figure 2.

Figure 2

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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).

However, RTN chemoreceptors retain approximately half their serotonin sensitivity when KCNQ channels are blocked (Hawryluk et al. 2012), suggesting involvement of other channels. Recent evidence reports that residual serotonin sensitivity during KCNQ channel blockade can be eliminated by inhibiting HCN channels (Hawkins et al. 2014). Considering that HCN channels are an important component of the pacemaking mechanism of embryonic parafacial neurons which presumably evolve into adult RTN chemoreceptors (Thoby-Brisson et al. 2009), it is not surprising that HCN channels also regulate the activity of mature RTN chemoreceptors. Furthermore, HCN channels are known to be activated by cAMP and Gs-coupled receptor signalling (Biel et al. 2009), and evidence suggests that ketanserin can inhibit Gs-coupled 5-HT7 (Jasper et al. 1997), albeit at a lower affinity than 5-HT2 receptors. We recently confirmed this possibility ex vivo by showing that serotonin sensitivity was reduced by blocking 5-HT7 receptors or downstream adenylate cyclase activity (Hawkins et al. 2014). Therefore, we propose that 5-HT7 receptors and HCN channels contribute to the effects of serotonin on chemosensitive RTN neurons, and in conjunction with Gq-mediated inhibition of KCNQ, together these cascades ensure a robust serotonin response.

Physiological significance

SUDEP is a leading cause of death among epilepsy patients (Massey et al. 2014), thus making SUDEP a major public health concern. The cellular and molecular mechanisms underlying SUDEP are unknown. However, since respiratory problems have been reported in most witnessed cases of SUDEP (Langan et al. 2000; Devinsky, 2011) and clinical studies commonly observe apnoea during and after seizures (Nashef et al. 1996; Sowers et al. 2013), respiratory dysfunction is thought to be an underlying cause of SUDEP (Devinsky, 2011; Massey et al. 2014). In addition, serotonin is a potent modulator of breathing (Richerson, 2004; Hodges et al. 2009; Ray et al. 2011; Hawryluk et al. 2012) and administration of selective serotonin reuptake inhibitors has been shown to improve breathing and decrease SUDEP-like deaths in an animal model of epilepsy (Faingold et al. 2011, 2014), thus suggesting that disruption of serotonergic signalling contributes to respiratory problems associated with SUDEP. We have recently shown that KCNQ channels regulate basal activity and serotonergic modulation of chemosensitive RTN neurons (Hawryluk et al. 2012). Considering that loss of functional KCNQ2 or KCNQ3 channels can cause certain types of epilepsy (Jentsch, 2000), including those associated with SUDEP (Weckhuysen et al. 2013), we propose that KCNQ2 and KCNQ3 channels represent a common substrate for epilepsy and respiratory problems associated with SUDEP. Furthermore, given the profound influence that KCNQ channels have on RTN chemoreceptors and the role that serotonergic dysfunction has in respiratory failure, KCNQ channels may represent useful therapeutic targets for the treatment of respiratory control disorders.

Acknowledgments

We thank the organizers of the 1st PanAmerican Congress of Physiological Sciences for giving us the opportunity to participate in this symposium.

Glossary

Abbreviations

HCN channel

hyperpolarization-activated cyclic nucleotide-gated channel

mAHP

medium afterhyperpolarization

RTN

retrotrapezoid nucleus

SK channel

Ca2+-activated K+ channel

SUDEP

sudden unexplained death in epilepsy

TASK

TWIK-related acid-sensitive potassium channel

THIK-1

TWIK-related halothane-inhibited K(+) channel

TWIK

Tandem of pore domain Weakly Inward rectifying K+ channel

Biographies

Daniel K.Mulkey received a PhD from the Department of Physiology and Biophysics atWright State University in 2002, and he was a postdoctoral fellow in the Department of Pharmacology at theUniversity of Virginia before joining the Department of Physiology and Neurobiology at the University of Connecticut in 2007. His current research focuses on understanding how the brain controls breathing at the molecular, cellular and network levels.

Virginia E.Hawkins obtained her PhD with Arthur M. Butt at the University of Portsmouth working on K+ channels and neuron–glial interactions in the CNS. Currently she is investigating the role of both glial and neuronal ion channels in the central control of breathing as a postdoctoral fellow with Daniel K. Mulkey at the University of Connecticut.

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Additional information

Competing interests

None declared.

Funding

This work was supported by funds from the National Institutes of Health (grants HL104101 to D.K.M. and NS073981 to A.V.T.), public funding from the São Paulo Research Foundation (FAPESP) (grants 13/10573-8 and 09/54888-7 to T.S.M., and 10/09776-3 to A.C.T.), and grants from Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq) (471744/2011-5 and 471263/2013-3 to A.C.T., and 471283/2012-6 to T.S.M.).

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