Fast transient A-type K+ currents (IA), such as the subthreshold-activating somato-dendritic A-type K+ currents in neurons (ISA) and the fast transient outward K+ current in cardiac ventricular myocytes (Ito) are essential for the proper functioning of the brain and the heart. During pathological conditions, abnormalities in these currents can contribute to disease conditions, as recently found in a patient with temporal lobe epilepsy. This project addresses the molecular nature of the ion channels responsible for the generation of these currents in mammalian neurons. It seeks to establish the molecular composition of these channels and to elucidate the physiological significance of the identified components. Work supported by this grant led to the discovery of a novel family of proteins that associates with ISA channels known as DPPLs, of which two members are currently known DPPX (or DPP6) and DPP10. It is now believed that ISA channels in neurons are ternary complexes that include principal or pore-forming subunits of the Kv4 family and two types of associated proteins KChIPs and DPPLs. This application is focused in CA1 hippocampal pyramidal cells, neurons that are important in spatial learning and in the pathogenesis of epilepsy, and prominently express one Kv4 protein Kv4.2 and one DPPL, DPPX. The goal of the proposal is to test the hypothesis that DPPX is an important component of Kv4 channels in CA1 neurons, determining the proper distribution, biophysical properties and dynamic modulation of the channels.
Aim 1 will utilize highly specific antibodies raised during the last funding period to investigate the localization of DPPX in CA1 neuron dendrites and its relationship to the other Kv4 channel components.
Aim 2 will utilize DPPX knockout mice also developed during the last funding period to investigate the effects of DPPX ablation on the distribution and function of Kv4 channels in CA1 neurons.
Aim 3 explores aspects of DPPX actions on Kv4 channels that have thus far received little attention: the effects of this auxiliary subunit on channel modulation by protein kinases and in controlling channel trafficking and expression in the plasma membrane, to test the hypothesis that DPPX regulates the stability of Kv4 channels at the plasma membrane. Mutations in the gene encoding DPPX have been associated with autism, underscoring the importance of understanding the function of these proteins.

Public Health Relevance

This project investigates the relevance of newly discovered components of ion channels in brain neurons that are important in learning, pain control and the pathogenesis of epilepsy and autism.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS045217-10
Application #
8423012
Study Section
Biophysics of Neural Systems Study Section (BPNS)
Program Officer
Silberberg, Shai D
Project Start
2002-12-01
Project End
2015-02-28
Budget Start
2013-03-01
Budget End
2015-02-28
Support Year
10
Fiscal Year
2013
Total Cost
$350,648
Indirect Cost
$143,776
Name
New York University
Department
Physiology
Type
Schools of Medicine
DUNS #
121911077
City
New York
State
NY
Country
United States
Zip Code
10016
Kang, Wenfei; Balordi, Francesca; Su, Nan et al. (2014) Astrocyte activation is suppressed in both normal and injured brain by FGF signaling. Proc Natl Acad Sci U S A 111:E2987-95
Xu, Han; Jeong, Hyo-Young; Tremblay, Robin et al. (2013) Neocortical somatostatin-expressing GABAergic interneurons disinhibit the thalamorecipient layer 4. Neuron 77:155-67
Lin, Lin; Sun, Wei; Throesch, Ben et al. (2013) DPP6 regulation of dendritic morphogenesis impacts hippocampal synaptic development. Nat Commun 4:2270
Goldberg, Ethan M; Jeong, Hyo-Young; Kruglikov, Ilya et al. (2011) Rapid developmental maturation of neocortical FS cell intrinsic excitability. Cereb Cortex 21:666-82
Sun, Wei; Maffie, Jon K; Lin, Lin et al. (2011) DPP6 establishes the A-type K(+) current gradient critical for the regulation of dendritic excitability in CA1 hippocampal neurons. Neuron 71:1102-15
Fishell, Gord; Rudy, Bernardo (2011) Mechanisms of inhibition within the telencephalon: "where the wild things are". Annu Rev Neurosci 34:535-67
Zagha, Edward; Manita, Satoshi; Ross, William N et al. (2010) Dendritic Kv3.3 potassium channels in cerebellar purkinje cells regulate generation and spatial dynamics of dendritic Ca2+ spikes. J Neurophysiol 103:3516-25
Lee, SooHyun; Hjerling-Leffler, Jens; Zagha, Edward et al. (2010) The largest group of superficial neocortical GABAergic interneurons expresses ionotropic serotonin receptors. J Neurosci 30:16796-808
Constantinople, Christine M; Disney, Anita A; Maffie, Jonathan et al. (2009) Quantitative analysis of neurons with Kv3 potassium channel subunits, Kv3.1b and Kv3.2, in macaque primary visual cortex. J Comp Neurol 516:291-311
Maffie, Jonathon; Blenkinsop, Timothy; Rudy, Bernardo (2009) A novel DPP6 isoform (DPP6-E) can account for differences between neuronal and reconstituted A-type K(+) channels. Neurosci Lett 449:189-94

Showing the most recent 10 out of 25 publications