The intrinsic rhythmicity of spike-burst generation in pancreatic β-cells and intercellular interaction within an islet

Abstract

The pancreatic β-cell has four types of Ca2+ channel (L-type, T-type, low-threshold slowly inactivating, and low-threshold non-inactivating Ca2+), although the low-threshold non-inactivating Ca2+ channel has not yet been confirmed experimentally. Beside these, there are at least three types K+ channels (K((ATP)), K((Ca,V)), and K((V))), and transporters (GLUT-2, Na+/Ca2+-countertransporter, and Na+/K+-pump) as schematically shown in Fig. 4. Opinions on the mechanism of spike-burst are converging to the following view: At intermediate glucose concentrations, the intracellular ATP/ADP ratio oscillates in the following way. A gradual rise in the ATP/ADP ratio causes gradual progression of depolarization to the threshold for the low-threshold Ca2+ channels, of which the opening causes regenerative depolarization to the plateau potential on which spikes (the L-type Ca2+ channel contributes to spike firing) are superimposed. During the active phase, a fall in the ATP/ADP ratio follows a gradual rise in ATP consumption. Slight repolarization due to the opening of a small fraction of K((ATP)) channels triggers regenerative repolarization. With the progress of repolarization, a residual fraction of voltage-gated Ca2+ channels (low-threshold non-inactivating) are deactivated. During the silent phase, a gradual rise in the ATP/ADP ratio leads to gradual depolarization back to the threshold for the next spike-burst, There are still a diversity of views regarding the mechanism of the initial spike-train. On the basis of observations made in various laboratories including ours, we propose the following working model: At low concentrations of glucose, α-cells secret glucagon which induces a rise in cAMP in β-cells lodged in the same islet. A rise in cAMP itself does not activate the enzymes relevant to glycogenolysis, but merely prepares to activate the enzymes. When extracellular glucose increases, Ca2+ spikes are elicited. Influxed Ca2+ ions, together with cAMP, work to activate the enzymes, resulting in an additional supply of fuel for ATP synthesis. After sometime, the cAMP level falls back to a low level and the additional glucose supply from stored glycogen stops. This reaction sequence may be the mechanism behind the initial spike-train. To substantiate this working model, it may be important to elucidate the dependence of the phosphorylasekinase and glycogenphosphorylase activities on the Ca2+ in β-cells.