In the nervous system, neurons generate and transmit electrical signals in response to various stimuli, ultimately yielding a behavioral response. These electrical signals are conducted by ion channels, which form pores in the cellular membrane and open to allow ions to pass through. Although electrical excitability is considered to be an inherent property of all neurons, we have recently discovered that, in order to conduct sodium ions, sensory neurons require chemical signals derived from non-neuronal cells known as glia. This proposal aims to identify the small organic molecule(s) responsible for this unique glial-neuron interaction and uncover the biochemical mechanism(s) that regulate the electrical signaling of neurons. Our proposed studies combine chemical, genetic, electrophysiological, biochemical, and cell biology approaches to gain insight into this regulatory pathway. We will use state-of-the-art techniques for purifying and culturing neurons and glia, and we will design novel molecular probes for labeling and imaging sodium ion channels to examine how their function is influenced by glia. Sodium ion channels have a prominent role in electrical signaling, and aberrant expression of this transmembrane protein has previously been linked to pain perception. Therefore, understanding how glia regulate the expression and/or post-translational modification of sodium ion channels may lead to the identification of new pharmaceutical targets for the treatment of pain.