In addition to regulating the firing patterns of neurons and other excitable cells, certain ion channels participate in """"""""non-conducting"""""""" functions that allow them directly to influence cellular signaling pathways. The Slack K+ channel is activated by elevations of intracellular Na+, and is expressed at high levels throughout the nervous system, including neurons that secrete neuropeptides. Activity dependent increases in the rate of neuropeptide synthesis have been found to be Na+-dependent, but the sensor that detects changes in Na+ is not known. The experiments in this proposal will test the hypothesis that the large-C-terminal Na+-dependent domain of Slack represents such a sensor. For these experiments we shall use the bag cell neurons of Aplysia, a model system of peptidergic neurons. In these cells, neuropeptide synthesis is known to be dependent on Na+ ions and stimulation of neuronal discharges produces a Na+-dependent increase in translation of mRNA encoding a neuropeptide precursor. Experiments will use biochemical, imaging and electrophysiological approaches to test the hypothesis that interactions between Slack channels and intracellular proteins that control local protein translation regulate the rate of translation or trafficking of messenger RNA for this neuropeptide precursor. Because defects in local protein translation have been proposed to contribute to genetic deficits that lead to mental retardation, an understanding of the role of Slack channels in the regulation of neuropeptide synthesis may lead to novel treatments for abnormalities of neuronal development, as well as of disorders of neuronal excitability.
Inherited loss or deficits in the Fragile X Mental Retardation Protein (FMRP) are the leading cause of inherited mental retardation, affecting one in 4000 males and one in 6000 females. Experiments in this proposal will determine the interactions between the FMRP protein and Slack proteins. The latter are a class of ion channels that interact with and may regulate the FMRP, which in turn controls the synthesis of new proteins in nerve cells. In addition, Slack channels are sodium-activated potassium channels that have been shown to protect cells from hypoxic injury. An impairment of the supply of oxygen or blood to cardiac cells and nerve cells leads to a variety of conditions including stroke, angina and myocardial infarctions. Lack of oxygen in newborns also results in serious brain injury leading to mental retardation. Thus pharmacological manipulations of Slack channels and their interactions with FMRP are likely to be therapeutically useful in the prevention of cell damage during stroke and myocardial infarction, and, in newborns, of the nerve cell damage that results in mental retardation.
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