The GABAA receptor is unique in that its activation can either excite or inhibit neurons. The ability of the GABAA receptor to switch between excitation and inhibition is a key feature of a surprising number of neural processes, including neocortical development, thalamocortical oscillations, circadian rhythm generation, the response of nerve cells to both trauma and prolonged seizures, and the perception of pain. Variations in GABAA function within a given population may occur both acutely and over more protracted periods of time. The dual effect of GABA in these systems is made possible by changes in the reversal potential for Cl-, the ion that carries the majority of the GABAA receptor-mediated postsynaptic current. Neurons alter the Cl- reversal potential (E(Cl)) by changing the intracellular Cl- concentration [Cl-]in. Neuronal Cl- homeostasis is mediated by a variety of passive and active mechanisms such as anion exchange, voltage-gated anion channels, and cation-Cl- cotransporters. In particular, the family of cation-Cl- cotransporters has the capability to efficiently move Cl- into or out of cells depending on which specific cotransporter predominates. In the peripheral and central nervous systems specific cation-Cl cotransport proteins have been identified: KCC1 and KCC2 move Cl- out of the cytoplasm while NKCC-2 moves Cl- into the cytoplasm. This proposal is designed to investigate the hypothesis that changes in intracellular Cl initiated by a variety of processes are primarily effected by two molecular mechanisms: expression and post-translational regulation of neuronal Cl transport gene products. We propose to first test the hypothesis that the regulation of [Cl-]in is due to the balanced expression of inwardly and outwardly directed Cl- transport proteins. We will then examine how specific second-messenger signal transduction pathways regulate the direction and rate of Cl- transport. Discovering how the family of cation-Cl- cotransporter genes maintains [Cl-]in and thereby determines whether GABAA activation is excitatory or inhibitory can lead to the identification of novel and highly specific therapeutic strategies, which will have special application to a broad spectrum of pathologies, including the treatment of seizures, modulation of sleep, amelioration of pain and spasticity, and may give new insight into neuronal responses to neurotrauma.
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