Ion Channel Pharmacology for Pain and Epilepsy

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Project Summary/ Abstract The proposed work will integrate two long-standing lines of research in the laboratory. One is to understand is to understand how the many types of ion channels present in a single neuron work together to regulate its firing pattern. In earlier grant periods, we focused on the individual gating behavior and functional roles of various kinds of calcium channels, sodium channels, and potassium channels in different kinds of mammalian neurons. More recently, we have tried to understand how the currents through the many kinds of channels in a given neuronal type interact, often in surprising ways, to control the firing pattern of the neuron. In a second line of research, we have characterized a variety of pharmacological agents that are targeted to voltage-dependent channels. Much of this work originally focused on finding peptide toxins and small molecules useful for separating components of current from specific channel types. Our goal now is to use our expanding knowledge about the differences in ion channel make-up of different kinds of neurons to rationally design novel compounds that can inhibit (or enhance) activity of specific kinds of neurons. Hypothesizing that it is no accident that many clinically- effective drugs act on multiple ion channels, we will attempt to design single compounds deliberately designed to inhibit or enhance specific combinations of voltage-dependent sodium, potassium, and calcium channels to differentially depress (or enhance) firing of specific neuronal types of interest, including primary nociceptors, hippocampal and cortical pyramidal neurons, various populations of cortical and hippocampal GABAergic neurons, and spinal cord motor neurons, in ways designed to have clinically beneficial effects. A key element of our approach is realizing that almost all small-molecule compounds targeted to voltage-dependent channels interact differentially with different gating states of the channels, resulting in complex dependence on voltage waveforms. Thus, differential inhibition of different neuronal types can be based on their different resting potentials, action potential shapes, and firing patterns as well as presence or absence of particular channel types being targeted. Our previous experience with a range of cell types, channel types, and channel-targeted drugs will provide a strong foundation for this effort.