KCNQ channels are key determinants of neuronal activity, and recent clinical evidence identifies mutations in KCNQ2 as a cause of neonatal epileptic encephalopathy. Most variants associated with neonatal epileptic encephalopathy are loss-of- function. However, recent work also identified a recurrent KCNQ2 gain-of-function mutation (R201C) in patients with neonatal- onset encephalopathy. Patients with both KCNQ2 loss- and gain-of-function mutations exhibit respiratory dysfunction including central hypoventilation syndrome, a condition thought to result from loss of respiratory chemoreception, i.e., the mechanism by which the brain regulates breathing in response to CO2/H+. The retrotrapezoid nucleus (RTN) is an important chemoreceptor region, and we have shown previously that KCNQ channels regulate basal activity and neurotransmitter modulation of RTN chemoreceptors. Therefore, we hypothesize that KCNQ2 channels are the principal KCNQ subunits that control activity of RTN chemoreceptors. We propose that KNCQ2 gain-of-function will hyperpolarize RTN chemoreceptors and eliminate their contribution to the drive to breathe, whereas KCNQ2 loss- of-function mutations will destabilize RTN chemoreceptor activity and disrupt modulation by neurotransmitters, thus also contributing to unstable breathing. Additionally, we will also test whether KCNQ2 dysfunction affects not only the RTN but the respiratory control circuit in general including other chemoreceptors, inspiratory rhythmogenic pre-Btzinger complex neurons, and output respiratory motor neurons. Objectives of this study are to investigate, from the cellular to system level, contributions of KCNQ2 channels to chemoreceptor function and respiratory control. The two Specific Aims of this project are: 1) determine cellular effects of KCNQ2 loss- and gain-of-function mutations on respiratory chemoreception, inspiratory rhythm generation and motor output and 2) determine the essential role of KCNQ2 channels in control of breathing. The rationale for the proposed research is that by understanding whether and how KCNQ2 channels regulate neuronal activity across multiple levels of the respiratory circuit, and respiratory behavior, we will lay a foundation for development of treatments for respiratory problems like apnea and central hypoventilation syndrome.
Loss- and gain-of-function mutations KCNQ2 channels are associated with neonatal- onset encephalopathy, and patients with this condition exhibit varying degrees of respiratory dysfunction including central hypoventilation syndrome, thus suggesting KCNQ2 channels regulate activity of neurons that drive breathing. To our knowledge KCNQ2 channels are the first K+ channels associated with respiratory dysfunction in a human disease. Despite the increased understanding of KCNQ2 in biology and the recent identification of KCNQ2 mutations from human patients, the genotype-phenotype relationship between KCNQ2 variants and respiratory dysfunction is currently unknown. Therefore, the goal of this application is to understand the essential role of KCNQ2 in control of breathing at the cellular, network and whole animal levels.
| Gonçalves, Christopher M; Mulkey, Daniel K (2018) Bicarbonate directly modulates activity of chemosensitive neurons in the retrotrapezoid nucleus. J Physiol 596:4033-4042 |
| Falquetto, Bárbara; Oliveira, Luiz M; Takakura, Ana C et al. (2018) Inhibition of the hypercapnic ventilatory response by adenosine in the retrotrapezoid nucleus in awake rats. Neuropharmacology 138:47-56 |
| Soh, Heun; Park, Suhyeorn; Ryan, Kali et al. (2018) Deletion of KCNQ2/3 potassium channels from PV+ interneurons leads to homeostatic potentiation of excitatory transmission. Elife 7: |
| Al-Naggar, Iman M; Hardy, Cara C; Taweh, Omar G et al. (2018) HCN as a Mediator of Urinary Homeostasis: Age-Associated Changes in Expression and Function in Adrenergic Detrusor Relaxation. J Gerontol A Biol Sci Med Sci : |
| Niday, Zachary; Tzingounis, Anastasios V (2018) Potassium Channel Gain of Function in Epilepsy: An Unresolved Paradox. Neuroscientist 24:368-380 |
