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.
|Tremblay, Robin; Lee, Soohyun; Rudy, Bernardo (2016) GABAergic Interneurons in the Neocortex: From Cellular Properties to Circuits. Neuron 91:260-92|
|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|
|Rossignol, Elsa; Kruglikov, Illya; van den Maagdenberg, Arn M J M et al. (2013) CaV 2.1 ablation in cortical interneurons selectively impairs fast-spiking basket cells and causes generalized seizures. Ann Neurol 74:209-22|
|Lin, Lin; Sun, Wei; Throesch, Ben et al. (2013) DPP6 regulation of dendritic morphogenesis impacts hippocampal synaptic development. Nat Commun 4:2270|
|Xu, Han; Jeong, Hyo-Young; Tremblay, Robin et al. (2013) Neocortical somatostatin-expressing GABAergic interneurons disinhibit the thalamorecipient layer 4. Neuron 77:155-67|
|Boronat, Anna; Gelfand, Jeffrey M; Gresa-Arribas, Nuria et al. (2013) Encephalitis and antibodies to dipeptidyl-peptidase-like protein-6, a subunit of Kv4.2 potassium channels. Ann Neurol 73:120-8|
|Rudy, Bernardo; Fishell, Gordon; Lee, SooHyun et al. (2011) Three groups of interneurons account for nearly 100% of neocortical GABAergic neurons. Dev Neurobiol 71:45-61|
|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|
|Fishell, Gord; Rudy, Bernardo (2011) Mechanisms of inhibition within the telencephalon: ""where the wild things are"". Annu Rev Neurosci 34:535-67|
|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|
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