The intrinsic electrophysiological properties of a neuron determine how that cell will transmit signals and process information. Therefore it is critical that developing neurons acquire electrophysiological properties appropriate for their normal function in mature neural networks. Compared to other developmental events, relatively little is known about this process. This research will examine the developmental expression of Ca-activated K+ currents (IK[ca]) in chick ciliary ganglion (CG) neurons. IK[ca] is an important current because it contributes to regulation of resting membrane potential, spike waveform, and repetitive spike discharge, and because it can be modulated by neurotransmitters in many types of cells. In CG neurons, the normal developmental expression of IK[ca] requires interactions with target tissues in the eye, and with preganglionic nerve terminals. This research will test the hypothesis that the target-derived factor regulating IK[ca] is an isoform of transforming growth factors (TGF-beta), and that the preganglionic nerve terminal-derived factor is an isoform of beta-neuregulin. It is further proposed that these factors induce posttranslational modifications that confer Ca2+-dependence onto preexisting IK[ca] channels; that these two factors produce synergistic effects; and that the simultaneous actions of both factors is required to achieve normal expression of a functional IK[ca]. The role of target-derived TGF-beta will be established by means of specific inhibitors, neutralizing antibodies and intraocular injection of antisense oligonucleotides. The biophysical properties of single IK[Ca] channels induced by beta-neuregulin and TGF-beta treatment, and the temporal nature of their individual and combined actions, will be examined with a view towards determining the molecular basis of the actions of these growth factors. Inappropriate expression of ionic channels could lead to a number of neurological and developmental abnormalities. Moreover, damaged neurons exhibit changes in ionic channel expression similar to changes that take place in developing neurons. TGF-beta and beta-neuregulins have been proposed as potential therapeutic agents for treatment of Parkinson's disease, stroke, multiple sclerosis, myasthenia gravis, and other neurological diseases. Thus, it is important to learn how these agents affect the functional properties of vertebrate neurons.
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