Adenosine is produced, released, taken up, and metabolized by virtually every cell in the body. Extracellular concentrations of adenosine in the brain increase in response to conditions of increased metabolic demand such as with hypoxia, hypoglycemia, or seizure-like activity. Adenosine has been shown to depress synaptic transmission by influencing both presynaptic and postsynaptic potassium and calcium channels as well as having other systemic effects related to potassium and calcium channel modulation such as vasodilation and negative changes in cardiac inotropy and chronotropy. Adenosine is one of the major neurotransmitters in the hippocampus. Because the hippocampus is an important structure in both learning and memory and is involved in many types of epilepsies, ion channel modulation by adenosine may play a significant role in regulating hippocampal electrical activity. However, the full extent of potassium and calcium channel modulation by activation of adenosine receptors and its implications are still unknown. The goals of this grant are four-fold. First, we will investigate what types of adenosine receptors are involved in ion channel modulation in the hippocampus. Second, the identification of potassium and/or calcium channels affected by selective receptor activation and characterization of this modulation will be explored. Third, coupling mechanisms involved between receptors and channels will be determined. Finally, given that particular receptors may alter calcium and potassium channels selectively, what is the impact of these membrane changes to physiological function and, in particular, to synaptic transmission. The question of presynaptic and postsynaptic channel modifications will be studied. The experiments proposed in this grant will be performed in both acutely isolated young adult guinea pig hippocampal neurons and in the hippocampal slice preparation where appropriate. Acutely isolated neurons permit excellent space clamp control for patch clamp experiments. Electrophysiological measurements of ion channel currents will use both the whole-cell and single-channel voltage clamp configurations. synaptic transmission will be measured using the standard microelectrode and slice-patch voltage clamp techniques for recording postsynaptic potentials and currents, respectively.
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