MOLECULAR BASIS OF MEMBRANE EXCITABILITY

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Essential to the function of nerve, heart and muscle cells is the rapid transmission of information encoded in the frequency and duration of electrical impulses called action potentials. Among excitable cells and even within a population of neurons, the maximal action potential firing frequency, and the shape and duration of those action potentials vary widely. The goal of this project is to understand these differences in terms of specific subtypes of voltage-gated ionic channels expressed by the cell. Ionic channels are membrane proteins that generate the action potential signal by regulating the flow of ions across the membrane. They come in a variety of types, that are typically named by the ion species that they are most selective for. Within the categories of Na, K and Ca channels, a rapidly increasing number of channel subtypes is being distinguished by biophysical, pharmacological or structural differences. Although rapid progress is being made in characterizing these differences and elucidating the underlying molecular structures, surprisingly little is known about how these subtype differences contribute to the essential functional differences of the cells in which they are expressed. This is especially true of Na channels which come in six or more subtypes, but which all seem at first glance to have the same function. An important clue comes from the distribution of these channel subtypes. In sensory neurons, the slow, TTX-insensitive (TTX-i) Na channels are always co-expressed with slowly- activating (slow) K channels, generating action potentials with relatively long durations. Conversely, fast-activating (fast) K channels are expressed only in cells that also express only the fast, TTX- sensitive (TTX-s) subtype of Na channel, generating short duration action potentials. A third subset of sensory neurons expresses only the TTX-s NA channel along with the slow K channel, generating action potentials of intermediate duration. The proposed research will investigate how the expression of these Na and K channel subtypes relates to the expression of specific Ca channel subtypes known to occur in these neurons. In addition, the functional implications of these ion channel subtype associations will be studied. For instance, how are the differences in action potential properties and dynamic firing characteristics exploited by different subsets of cells? Are there general principles that determine which subtypes of different channel species are co-expressed in the same cells? Are these principles and similar associations of related subtypes found in other tissues? Are these associations exploited in similar ways?