Insulinotropic effect of high potassium concentration beyond plasma membrane depolarization.
The question whether K⁺ depolarization is an appropriate experimental substitute for the physiological nutrient-induced depolarization of the β-cell plasma membrane was investigated using primary mouse β-cells and islets. At basal glucose 40 mM K⁺ induced a massive monophasic response, whereas 15 mM K⁺ had only a minimal insulinotropic effect, even though the increase in the cytosolic Ca²⁺ concentration ([Ca²⁺]i) was not inferior to that by 20 mM glucose. In voltage-clamp experiments, Ca²⁺ influx appeared as nifedipine-inhibitable inward action currents in the presence of sulfonylurea plus TEA to block compensatory outward K⁺ currents. Under these conditions, 15 mM K⁺ induced prolonged action currents and 40 mM K⁺ transformed the action current pattern into a continuous inward current. Correspondingly, 15 mM K⁺ led to an oscillatory increase and 40 mM K⁺ to a plateau of [Ca²⁺]i superimposed on the [Ca²⁺]i elevated by sulfonylurea plus TEA. Raising K⁺ to 15 or 40 mM in the presence of sulfonylurea (±TEA) led to a fast further increase of insulin secretion. This was reduced to basal levels by nifedipine or CoCl₂. The effects of 15 mM K⁺ on depolarization, action currents, and insulin secretion were mimicked by adding 35 mM Cs⁺ and those of 40 mM K⁺ by adding 35 mM Rb⁺, in parallel with their ability to substitute for K⁺ as permeant cation. In conclusion, the alkali metals K⁺, Rb⁺, or Cs⁺ concentration-dependently transform the pattern of Ca²⁺ influx into the β-cell and may thus generate stimuli of supraphysiological strength for insulin secretion.
Institute of Pharmacology and Toxicology, University of Braunschweig, Braunschweig, Germany.
M
M
Belz
M
M
Willenborg
N
N
Görgler
A
A
Hamada
K
K
Schumacher
I
I
Rustenbeck
D000818:Animals; D002121:Calcium Channel Blockers / Q000494:pharmacology; D020013:Calcium Signaling / Q000187:drug effects; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism*; D002478:Cells, Cultured; D002586:Cesium / Q000378:metabolism; D005947:Glucose / Q000378:metabolism; D007004:Hypoglycemic Agents / Q000494:pharmacology; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D007515:Islets of Langerhans / Q000187:drug effects / Q000378:metabolism; D008564:Membrane Potentials / Q000187:drug effects; D051379:Mice; D008815:Mice, Inbred Strains; D009994:Osmolar Concentration; D018408:Patch-Clamp Techniques; D011188:Potassium / Q000378:metabolism*; D026902:Potassium Channel Blockers / Q000494:pharmacology; D012413:Rubidium / Q000378:metabolism; D046509:Tissue Culture Techniques
D002121:Calcium Channel Blockers; D007004:Hypoglycemic Agents; C514817:Ins1 protein, mouse; D007328:Insulin; D026902:Potassium Channel Blockers; D002586:Cesium; D005947:Glucose; D012413:Rubidium; D011188:Potassium
adenosine 5′-triphosphate-sensitive potassium channel; cytosolic calcium concentration; pancreatic islets; plasma membrane potential