title: The intrinsic rhythmicity of spike-burst generation in pancreatic beta-cells and intercellular interaction within an islet.
abstract: The pancreatic beta-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 of K+ channels (K(ATP), K(Ca,V), and K(V)), and transporters (GLUT-2, Na+/Ca(2+)-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, alpha-cells secret glucagon which induces a rise in cAMP in beta-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 beta-cells.
authors.affiliation: Department of Physiology, Shiga University of Medical Science, Ohtsu, Japan. kitasato@belle.shiga-med.ac.jp
authors.forename: H
authors.initials: H
authors.lastname: Kitasato
authors.forename: R
authors.initials: R
authors.lastname: Kai
authors.forename: W G
authors.initials: WG
authors.lastname: Ding
authors.forename: M
authors.initials: M
authors.lastname: Omatsu-Kanbe
mesh_terms: D000109:Acetylcholine / Q000502:physiology; D000244:Adenosine Diphosphate / Q000502:physiology; D000255:Adenosine Triphosphate / Q000502:physiology; D015220:Calcium Channels / Q000502:physiology*; D002450:Cell Communication / Q000502:physiology*; D000242:Cyclic AMP / Q000502:physiology; D004553:Electric Conductivity; D005089:Exocytosis / Q000502:physiology; D005934:Glucagon / Q000502:physiology; D005947:Glucose / Q000378:metabolism; D006801:Humans; D007328:Insulin / Q000378:metabolism; D000078790:Insulin Secretion; D007515:Islets of Langerhans / Q000502:physiology*; D010507:Periodicity
chemical_list: D015220:Calcium Channels; D007328:Insulin; D000244:Adenosine Diphosphate; D000255:Adenosine Triphosphate; D005934:Glucagon; D000242:Cyclic AMP; D005947:Glucose; D000109:Acetylcholine