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.
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