title: KCNQ channels determine serotonergic modulation of ventral surface chemoreceptors and respiratory drive.
abstract: Chemosensitive neurons in the retrotrapezoid nucleus (RTN) regulate breathing in response to CO(2)/H(+) changes. Their activity is also sensitive to neuromodulatory inputs from multiple respiratory centers, and thus they serve as a key nexus of respiratory control. However, molecular mechanisms that control their activity and susceptibility to neuromodulation are unknown. Here, we show in vitro and in vivo that KCNQ channels are critical determinants of RTN neural activity. In particular, we find that pharmacological block of KCNQ channels (XE991, 10 μm) increased basal activity and CO(2) responsiveness of RTN neurons in rat brain slices, whereas KCNQ channel activation (retigabine, 2-40 μm) silenced these neurons. Interestingly, we also find that KCNQ and apamin-sensitive SK channels act synergistically to regulate firing rate of RTN chemoreceptors; simultaneous blockade of both channels led to a increase in CO(2) responsiveness. Furthermore, we also show that KCNQ channels but not SK channels are downstream effectors of serotonin modulation of RTN activity in vitro. In contrast, inhibition of KCNQ channel did not prevent modulation of RTN activity by Substance P or thyrotropin-releasing hormone, previously identified neuromodulators of RTN chemoreception. Importantly, we also show that KCNQ channels are critical for RTN activity in vivo. Inhibition of KCNQ channels lowered the CO(2) threshold for phrenic nerve discharge in anesthetized rats and decreased the ventilatory response to serotonin in awake and anesthetized animals. Given that serotonergic dysfunction may contribute to respiratory failure, our findings suggest KCNQ channels as a new therapeutic avenue for respiratory complications associated with multiple neurological disorders.
authors.affiliation: Department of Physiology and Neurobiology, University of Connecticut, Storrs, Connecticut 06269, USA.
authors.forename: Joanna M
authors.initials: JM
authors.lastname: Hawryluk
authors.forename: Thiago S
authors.initials: TS
authors.lastname: Moreira
authors.forename: Ana C
authors.initials: AC
authors.lastname: Takakura
authors.forename: Ian C
authors.initials: IC
authors.lastname: Wenker
authors.forename: Anastasios V
authors.initials: AV
authors.lastname: Tzingounis
authors.forename: Daniel K
authors.initials: DK
authors.lastname: Mulkey
mesh_terms: D000758:Anesthesia; D000818:Animals; D000831:Animals, Newborn; D001933:Brain Stem / Q000502:physiology*; D002219:Carbamates / Q000494:pharmacology; D002245:Carbon Dioxide / Q000502:physiology; D002628:Chemoreceptor Cells / Q000502:physiology*; D004328:Drive; D055724:Electrophysiological Phenomena; D066298:In Vitro Techniques; D051656:KCNQ Potassium Channels / Q000819:agonists / Q000037:antagonists & inhibitors / Q000502:physiology*; D008297:Male; D010655:Phenylenediamines / Q000494:pharmacology; D010791:Phrenic Nerve / Q000187:drug effects / Q000502:physiology; D051381:Rats; D015656:Respiratory Mechanics / Q000502:physiology*; D012701:Serotonin / Q000502:physiology*; D051640:Small-Conductance Calcium-Activated Potassium Channels / Q000378:metabolism; D013373:Substance P / Q000494:pharmacology; D013973:Thyrotropin-Releasing Hormone / Q000494:pharmacology
chemical_list: D002219:Carbamates; D051656:KCNQ Potassium Channels; D010655:Phenylenediamines; D051640:Small-Conductance Calcium-Activated Potassium Channels; C101866:ezogabine; D002245:Carbon Dioxide; D012701:Serotonin; D013373:Substance P; D013973:Thyrotropin-Releasing Hormone