The appropriate processing of information by mature neural networks, and even the formation of these networks, requires that individual neurons exhibit coherent temporal patterns of action potential discharge. The waveforms of individual action potentials, and the temporal patterns of discharge, are determined by the entire ensemble of ion channels expressed in the neuronal plasma membrane. Therefore, it is important to understand the factors that regulate the differentiation of neuronal excitability. Large-conductance Ca2-activated K+ channels (Kca channels) play an especially important role in the regulation of repetitive spike discharge in vertebrate neurons. This research will examine the intracellular mechanisms that underlie developmental regulation of channels by inductive cell-cell interactions and neurotrophic factors. This work is focused on an identified population of cells, the ciliary neurons of the chick ciliary ganglion. We have previously shown that transforming growth factor-beta1(TGF beta1) and beta-neuregulin-1 (beta-NEU1) are both required for the acquisition of functional Kca channels in ciliary neurons developing in vivo. These effects of TGFbeta1require activation of the MAP kinase Erk. In the first specific aim, we will determine the transduction cascades used by TGFbeta1 in ciliary neurons. We will determine if the acute effects of TGFbeta1 are mediated by insertion of preexisting Kca channels into the plasma membrane, and whether transduction is mediated by the small GTPases Ras and Rac. We will also identify the MAP kinase, PI3 kinase, and Smad pathways used by TGFb in the regulation of ciliary neuron Kca. channels. The second specific aim will focus on J3-NEU1, and will determine if this factor is required for maintenance as well as initial stimulation of Kca expression. We will also determine if the actions of b-NEU1 are transduced through MAP kinase and PI3 kinase cascades, and the steps in the intracellular transduction cascades that are subject to synergistic regulation by TGFbeta1 and betaNEU1. Neurotrophic factors are potential therapeutic agents for neurodegeneration. This research will provide additional information on neurotrophic factor actions and interactions, especially with respect to posttranslational effects.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Project (R01)
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Molecular, Cellular and Developmental Neurosciences 2 (MDCN)
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Stewart, Randall
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University of Houston
Schools of Arts and Sciences
United States
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Kim, Eun Young; Alvarez-Baron, Claudia P; Dryer, Stuart E (2009) Canonical transient receptor potential channel (TRPC)3 and TRPC6 associate with large-conductance Ca2+-activated K+ (BKCa) channels: role in BKCa trafficking to the surface of cultured podocytes. Mol Pharmacol 75:466-77
Jha, Smita; Dryer, Stuart E (2009) The beta1 subunit of Na+/K+-ATPase interacts with BKCa channels and affects their steady-state expression on the cell surface. FEBS Lett 583:3109-14
Kim, Eun Young; Choi, Kyoung-Jae; Dryer, Stuart E (2008) Nephrin binds to the COOH terminus of a large-conductance Ca2+-activated K+ channel isoform and regulates its expression on the cell surface. Am J Physiol Renal Physiol 295:F235-46
Zou, Shengwei; Jha, Smita; Kim, Eun Young et al. (2008) The beta 1 subunit of L-type voltage-gated Ca2+ channels independently binds to and inhibits the gating of large-conductance Ca2+-activated K+ channels. Mol Pharmacol 73:369-78
Zou, Shengwei; Jha, Smita; Kim, Eun Young et al. (2008) A novel actin-binding domain on Slo1 calcium-activated potassium channels is necessary for their expression in the plasma membrane. Mol Pharmacol 73:359-68
Kim, E Y; Ridgway, L D; Zou, S et al. (2007) Alternatively spliced C-terminal domains regulate the surface expression of large conductance calcium-activated potassium channels. Neuroscience 146:1652-61
Kim, Eun Young; Ridgway, Lon D; Dryer, Stuart E (2007) Interactions with filamin A stimulate surface expression of large-conductance Ca2+-activated K+ channels in the absence of direct actin binding. Mol Pharmacol 72:622-30
Kim, Eun Young; Zou, Shengwei; Ridgway, Lon D et al. (2007) Beta1-subunits increase surface expression of a large-conductance Ca2+-activated K+ channel isoform. J Neurophysiol 97:3508-16
Chae, Kwon-Seok; Oh, Kwang-Seok; Dryer, Stuart E (2005) Growth factors mobilize multiple pools of KCa channels in developing parasympathetic neurons: role of ADP-ribosylation factors and related proteins. J Neurophysiol 94:1597-605
Chae, Kwon-Seok; Dryer, Stuart E (2005) The p38 mitogen-activated protein kinase pathway negatively regulates Ca2+-activated K+ channel trafficking in developing parasympathetic neurons. J Neurochem 94:367-79

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