NEUROMODULATION OF ION CHANNELS

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One of the central challenges facing neurobiologists is to understand the cellular and molecular mechanisms that give rise to long-lasting alterations in behavior, such as learning and memory. This challenge has not yet been realized for any vertebrate neuronal system, but current models of learning invoke use-dependent alterations in the electrical properties of neurons, particularly at synapses. Because ion channels are the fundamental building blocks underlying all electrical signaling in excitable cells, any understanding of neuronal plasticity must include information about how the properties of ion channels can be modulated by these signaling molecules. The overall approach of this proposal is to determine the molecular mechanisms by which ion channels can respond to and integrate information carried by a multiple signaling molecules. Such integrative mechanisms are believed to be an important component in the expression of neuroplasticity, and endow neurons with the ability to respond uniquely to a changing environment. Ca2plus -activated Kplus (Kca) channels are a particularly useful and general model to study signal integration because they can be modulated by a number of intracellular signaling molecules, the channels are expressed in most if not all neurons in both cell bodies and at synapses, and they have a large unitary conductance facilitating electrophysiological recordings. We will use a combination of electrophysiological, molecular biological, and biochemical approaches to determine how ca2plus and protein kinases modulate human Kca channels, and test whether these channels can integrate multiple signaling pathways to function as molecular coincidence detectors. Specific questions addressed by this proposal are 1. How is an elevation in intracellular Ca2plus sensed and translated into channel opening by Kca channels?, 2. How are the effects of multiple protein kinases translated into K ca channel opening?, and 2, Can Kca channels function as molecular coincidence detectors that respond uniquely to the simultaneous activation of two or more signaling pathways? Our results will provide information on the mechanisms by which ion channels can act as coincidence detectors, and hence provide information on the molecular basis of neuroplasticity. Such information provides the basis for understanding higher order process such as learning and memory.