ISLET CELL ELECTRICAL PACEMAKER MECHANISMS

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Glucose-induced insulin release, a process known to be impaired in diabetes mellitus, involves a cascade of membrane electrical events, controlled by glucose, leading to the uptake of calcium ions trigger insulin release. Each electrical event is due to the gating of electrically charged ion flows across the cell membrane through specific ion conductance "channels". The channels carrying the calcium ions interact periodically and reciprocally with channels carrying potassium ions. Glucose is postulated to control calcium uptake by controlling the potassium channels. We have, therefore, established in our laboratory the recently developed "patch-clamp" method for studying single ionic channels in cell membranes. With this method we propose to 1) identify postassium channels in islet cell membranes and characterize their ionic and voltage dependence, 2) characterize the ability of glucose and certain glucose metabolites to control the activation of these potassium channels. Furthermore, we propose to relate the events at the cell membrane level to the activity of the whole cell in two ways. First, we have hypothesized that the periodicity of calcium and potassium channel activation depends, in large part, on the ability of the cell to buffer the periodic inflow of calcium. We propose to test this by measuring whole cell electrical responses to cyclic AMP, an endogenous agent known to interface with cellular calcium buffering. Second, we propose to determine the degree of coupling between the cellular calcium pool which controls insulin release and the pool which receives the gated calcium influx.