The long-term objective of this proposal is to understand the molecular mechanisms that regulate the function of mammalian A-type K+ channels. These K+ channels activate and inactivate rapidly in response to membrane depolarization, and one of their main functions is to control the neuronal interspike interval in episodes of repetitive firing. Thus, A-type K+ channels directly influence neuronal signal coding that underlies such complex mental processes as learning, memory and other cognitive functions. Two distinct cloned A-type K+ channels will be investigated: mouse brain channels encoded by mKv4.1 and human brain channels encoded by hKv3.4. They activate at membrane potentials negative or positive to the neuronal firing threshold, respectively.The mechanisms that regulate the function of these K+ channels have not been explored. A combination of recombinant DNA methodology (e.g., heterologous expression and mutagenesis in vitro) and electrophysiology (voltage-clamp and patch-clamp recording) will be used to address three aspects: First, the biophysical properties of A-type K+ channels encoded by mKv4.1, at the macroscopic and single channel levels. This information will serve as the basis for understanding regulation of channel function. Second, the molecular mechanisms of regulation of mouse and human A-type K+ channels by protein kinase C (PKC). Specific questions to address here are: i) how activation of PKC controls gating of specific K+ channels; ii) mapping of the phosphorylation site(s) involved; and iii) the significance of PKC as regulator of distinct A-type K+ channels in the nervous system. Third, the mechanisms that may regulate gating of A-type K+ channels (mKv4.1) in their native environment. Specifically exploring: i) how single K+ channels are fine tuned by putative native factors; and ii) strategies that may reveal the structural channel domains involved. Studying the molecular mechanisms that regulate the function of A-type K+ channels may enhance our understanding of brain functions impaired in neurological and psychiatric disorders.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Project (R01)
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Special Emphasis Panel (ZRG1-MDCN-3 (01))
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Talley, Edmund M
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Thomas Jefferson University
Schools of Medicine
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Wang, Guangyu (2017) Mechanistic insight into the heme-independent interplay between iron and carbon monoxide in CFTR and Slo1 BKCa channels. Metallomics 9:634-645
Fineberg, Jeffrey D; Szanto, Tibor G; Panyi, Gyorgy et al. (2016) Closed-state inactivation involving an internal gate in Kv4.1 channels modulates pore blockade by intracellular quaternary ammonium ions. Sci Rep 6:31131
Fineberg, Jeffrey D; Ritter, David M; Covarrubias, Manuel (2012) Modeling-independent elucidation of inactivation pathways in recombinant and native A-type Kv channels. J Gen Physiol 140:513-27
Bahring, Robert; Covarrubias, Manuel (2011) Mechanisms of closed-state inactivation in voltage-gated ion channels. J Physiol 589:461-79
Santiago-Castillo, Jose A De; Covarrubias, Manuel; Sanchez-Rodriguez, Jorge E et al. (2010) Simulating complex ion channel kinetics with IonChannelLab. Channels (Austin) 4:422-8
Dougherty, Kevin; Tu, Liwei; Deutsch, Carol et al. (2009) The dipeptidyl-aminopeptidase-like protein 6 is an integral voltage sensor-interacting beta-subunit of neuronal K(V)4.2 channels. Channels (Austin) 3:122-8
Kaulin, Yuri A; De Santiago-Castillo, José A; Rocha, Carmen A et al. (2009) The dipeptidyl-peptidase-like protein DPP6 determines the unitary conductance of neuronal Kv4.2 channels. J Neurosci 29:3242-51
Jerng, Henry H; Dougherty, Kevin; Covarrubias, Manuel et al. (2009) A novel N-terminal motif of dipeptidyl peptidase-like proteins produces rapid inactivation of KV4.2 channels by a pore-blocking mechanism. Channels (Austin) 3:448-61
Schwenk, Jochen; Zolles, Gerd; Kandias, Nikolaos G et al. (2008) NMR analysis of KChIP4a reveals structural basis for control of surface expression of Kv4 channel complexes. J Biol Chem 283:18937-46
Dougherty, Kevin; De Santiago-Castillo, Jose A; Covarrubias, Manuel (2008) Gating charge immobilization in Kv4.2 channels: the basis of closed-state inactivation. J Gen Physiol 131:257-73

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