ABSTRACT
Ion channels have an integral role to play in governing the release of insulin from the P-cells of the pancreatic islets of Langerhans. These cells synthesise, store and subsequently release insulin in response to a number of nutrient, hormonal, and neural stimuli. The major physiological regulator of insulin secretion is an increase in the plasma glucose concentration, which mediates its effects through an increase in the intracellular concentration of calcium ions ([Ca2 + ]J. This is associated with Ca2 + influx across the plasma membrane, and not mobilisation of Ca2 + from intracellular calcium stores (Wollheim and Sharp, 1981). To adjust the rate of insulin release in response to fluctuations in the availability of glucose, the P-cell has adopted several discrete control mechanisms to regulate [Ca2 + l-The most striking of these is a complex pattern of electrophysiological events that invokes changes in the P-cell membrane potential, and the remodelling of ionic fluxes across the plasma membrane, and intracellular membrane systems (see Figure 13.1). When the concentration of glucose is below that required to elicit insulin secretion, the membrane potential is silent and generally found to rest between -60 and -70 m V. This is determined by a high resting K + permeability, maintained by the Na + -K +- A TPase and open K ion channels. Raising the glucose concentration above the threshold for secretion (>7 mM), promotes a slow depolarisation of the membrane, which brings the P-cell to a critical threshold potential at which electrical activity is initiated. With conventional microelectrodes the patterns of responses were first characterised in the late 1960s/early 1970s (Dean and Matthews 1968, Matthews and Sakamoto 1975; Henquin, 1978, 1979). These basic changes in cell membrane potential have been extensively reviewed elsewhere (see Henquin and Meissner, 1984). In brief, the overall pattern is one of cycles, or slow waves of depolarisation and hyperpolarisation of the membrane culminating in the generation of plateau potentials with superimposed voltage-dependent Ca2+-spikes, (Figure 13.1). The inter-burst period is not strictly 'silent' since the membrane undergoes a slow 5-10 mV depolarisation. The function of this is to bring the cell to threshold from which a rapid depolarisation can again be initiated. For cell signalling, the most
important events occur during the quasi-sustained plateau potential since each voltage-dependent spike results from Ca2 + influx across the membrane (Dean and Matthews 1968; Wollheim and Sharp, 1981; Henquin and Meissner, 1984; Henquin, 1990). This occurs through voltage-gated Ca selective ion channels - the activities of which are closely guarded by the change in the cell membrane potential. In this manner, changes in the ,8-cell electrophysiology provide the mechanism for linking glucose metabolism, to an increase in [Ca 2 + ] ; (Santos et a/., 1991) and the subsequent release of insulin from the cells by exocytosis.
