A role for Ca2+-sensitive nonselective cation channels in regulating the membrane potential of pancreatic beta-cells.
The incretin hormones, glucagon-like peptide 1 and pituitary adenylyl cyclase-activating polypeptide, are proposed to activate a maitotoxin (MTX)-sensitive, Ca2+-dependent nonselective cation current in pancreatic beta-cells and insulinoma cells. This MTX-sensitive current is present in human beta-cells as well as in mouse and rat beta-cells, and is accompanied by a rise in cytosolic Ca2+ in voltage-clamped cells in which the activation of voltage-dependent Ca2+ channels is prevented. Activation of the nonselective cation current is inhibited by reduction of disulfide bonds with intracellular, but not extracellular, dithiothreitol, and is also abolished by intracellular dialysis with trypsin. The nonselective cation channels that carry this current have a conductance of about 30 pS, with Na+ as the major extracellular cation. We estimate that these cation channels are expressed on beta-cells at a density similar to that of ATP-sensitive potassium channels (K(ATP) channels) and exhibit spontaneous activity at basal glucose concentrations. We propose that this spontaneous cation channel activity constitutes at least part of the depolarizing background conductance that permits changes in the activity of K(ATP) channels to regulate the resting potential of beta-cells.
Leech
C A
CA
Laboratory of Molecular Endocrinology, Howard Hughes Medical Institute, Harvard Medical School, Massachusetts General Hospital, Boston 02114-2696, USA. leech@helix.mgh.harvard.edu
Habener
J F
JF
D000255:Adenosine Triphosphate / Q000494:pharmacology; D000818:Animals; D002118:Calcium / Q000378:metabolism / Q000494:pharmacology*; D002412:Cations; D002462:Cell Membrane / Q000502:physiology*; D004220:Disulfides / Q000378:metabolism; D004229:Dithiothreitol / Q000494:pharmacology; D004553:Electric Conductivity; D005934:Glucagon / Q000494:pharmacology; D052216:Glucagon-Like Peptide 1; D006801:Humans; D007473:Ion Channels / Q000502:physiology*; D007476:Ionophores / Q000494:pharmacology; D007515:Islets of Langerhans / Q000187:drug effects / Q000502:physiology* / Q000648:ultrastructure; D008387:Marine Toxins / Q000494:pharmacology; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology; D051379:Mice; D035964:Oxocins; D010446:Peptide Fragments / Q000494:pharmacology; D015221:Potassium Channels / Q000378:metabolism; D011498:Protein Precursors / Q000494:pharmacology; D014357:Trypsin / Q000494:pharmacology; D014407:Tumor Cells, Cultured; D000095702:Polyether Toxins
D000255:Adenosine Triphosphate; D002118:Calcium; D002412:Cations; D004220:Disulfides; D004229:Dithiothreitol; D005934:Glucagon; D052216:Glucagon-Like Peptide 1; D007473:Ion Channels; D007476:Ionophores; D008387:Marine Toxins; D035964:Oxocins; D010446:Peptide Fragments; D015221:Potassium Channels; D011498:Protein Precursors; D014357:Trypsin; C020394:maitotoxin; D000095702:Polyether Toxins