GABA-B Receptor Modulation of Calcium Currents

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DESCRIPTION (provided by applicant): The long range goal of the laboratory is to enhance our understanding of how neurotransmitters modulate calcium channel activity and the functional consequences of this modulation. The main inhibitory neurotransmitter in the mammalian central nervous system, gamma-aminobutyric acid (GABA) is known to attenuate N-type calcium currents by activation of GABA-B receptors. A unique finding in our laboratory is that L-type current is facilitated in response to GABA-B receptor activation in the neonatal neurons of the rat hippocampus. Understanding the mechanisms and functional significance of this facilitation will have significant consequences for the treatment of diseases such as drug addiction, epilepsy, insomnia and anxiety that are routinely treated with compounds interacting with the GABAergic system. The central hypothesis to be tested is that GABA-B receptor mediated facilitation of L-type current in the superior region of the hippocampus is medfy the signal transduction mechanism of the facilitation of L-type calcium current by activation of GABAB receptors. Specific aim #2 is to determine the specific subcellular location of the L-type calcium channels facilitated by GABAB receptors. Specific aim #3 is to determine whether or not activation of GABAB receptors contributes to the increase in potassium coupled chloride transporter expression seen early in neonatal development. The experiments outlined in this proposal will use whole cell and single channel recording, ratiometric calcium imaging, immunocytochemistry and Western blot analysis of proteins to accomplish the aims of the proposal. The experiments outlined in this proposal will provide knowledge about the signal transduction mechanism underlying the facilitation of L-type current and will begin to investigate the functional significance of this effect by identifying the subcellular location as well as the role in up-regulation of chloride transporter expression in the first two postnatal weeks in the rat hippocampus. A better understanding of the GABA-B receptor function may allow more subtle manipulation of the GABAergic system allowing for better design of pharmaceuticals with fewer side effects.