The KCNQ channel family includes five genes, known as Kcnq1-5. Most family members are required for proper function of either the nervous or cardiovascular system as loss of function mutations in Kcnq genes lead to LQTS syndrome (Kcnq1), progressive hearing loss (Kcnq4) and benign familial neonatal convulsions (BFNC), a pediatric epilepsy (Kcnq2, Kcnq3). KCNQ2/3 heteromeric channels are thought to mediate the M-current, a sub-threshold activating potassium conductance that controls the excitability of CNS neurons. However, unlike KCNQ3 channels, more than 90% of mutations related to the BFNC are mapped to the Kcnq2 gene locus and Kcnq2 knockout mice die within 24 hours after birth. Thus, Kcnq2 may either be the primary KCNQ subunit in the brain or it may play a unique role in additional physiological processes. Our long-term goal is to understand the in vivo functions of KCNQ channels and how mutations in these channels lead to epileptogenesis. The overall goal of this project is to determine the role of KCNQ2 channels in controlling intrinsic neuronal excitability. To achieve our objective we will combine pharmacology, protein engineering, genetics, and electrophysiology. Using these approaches we will first establish the functional contribution of KCNQ2 channels to the M-current across development using a recently identified KCNQ2-specific inhibitor. We will subsequently test whether KCNQ2 channels underlie multiple conductances in the brain using gain-of-function mutations and novel pharmacology. Lastly, we will test the role of KCNQ2 channels in regulating resting and active membrane properties using Kcnq2 conditional knockout mice. These studies will be conducted in mouse brain slices using current- and voltage-clamp recordings. We will use hippocampus as a model brain area because it is implicated in epilepsy and learning and memory. The results from these studies will provide insight into an important potassium channel that plays a fundamental role in limiting unchecked neuronal activity and seizures in the brain.

Public Health Relevance

Dysfunction of the potassium channel KCNQ2 leads to the pediatric epilepsy benign familial neonatal convulsions, but the mechanisms by which these channels affect neuronal activity are not well-understood. Our goal is to unravel the precise physiological role KCNQ2 channels play in the normal brain. Such work will provide an improved understanding of innate mechanisms that prevent epileptogenesis and could lead to the development of novel anti-epileptic drugs.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS073981-05
Application #
8820092
Study Section
Neurotransporters, Receptors, and Calcium Signaling Study Section (NTRC)
Program Officer
Silberberg, Shai D
Project Start
2011-03-01
Project End
2016-06-30
Budget Start
2015-03-01
Budget End
2016-06-30
Support Year
5
Fiscal Year
2015
Total Cost
Indirect Cost
Name
University of Connecticut
Department
Physiology
Type
Schools of Arts and Sciences
DUNS #
614209054
City
Storrs-Mansfield
State
CT
Country
United States
Zip Code
Niday, Zachary; Tzingounis, Anastasios V (2018) Potassium Channel Gain of Function in Epilepsy: An Unresolved Paradox. Neuroscientist 24:368-380
Abiraman, Krithika; Tzingounis, Anastasios V; Lykotrafitis, George (2018) KCa2 channel localization and regulation in the axon initial segment. FASEB J 32:1794-1805
Zhang, Yihao; Abiraman, Krithika; Li, He et al. (2017) Modeling of the axon membrane skeleton structure and implications for its mechanical properties. PLoS Comput Biol 13:e1005407
Niday, Zachary; Hawkins, Virginia E; Soh, Heun et al. (2017) Epilepsy-Associated KCNQ2 Channels Regulate Multiple Intrinsic Properties of Layer 2/3 Pyramidal Neurons. J Neurosci 37:576-586
Tzingounis, Anastasios V (2017) SMITten for KCNQ Channels. Biophys J 113:503-505
Abiraman, Krithika; Sah, Megha; Walikonis, Randall S et al. (2016) Tonic PKA Activity Regulates SK Channel Nanoclustering and Somatodendritic Distribution. J Mol Biol 428:2521-2537
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Kalappa, Bopanna I; Soh, Heun; Duignan, Kevin M et al. (2015) Potent KCNQ2/3-specific channel activator suppresses in vivo epileptic activity and prevents the development of tinnitus. J Neurosci 35:8829-42
Mulkey, Daniel K; Hawkins, Virginia E; Hawryluk, Joanna M et al. (2015) Molecular underpinnings of ventral surface chemoreceptor function: focus on KCNQ channels. J Physiol 593:1075-81
Hawkins, Virginia E; Hawryluk, Joanna M; Takakura, Ana C et al. (2015) HCN channels contribute to serotonergic modulation of ventral surface chemosensitive neurons and respiratory activity. J Neurophysiol 113:1195-205

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