Dynamics of the cationic, bioelectrical and secretory responses to formycin A in pancreatic islet cells.
The dynamics of the cationic, bioelectrical and secretory responses to formycin A were monitored in pancreatic islet cells in order to assess whether this adenosine analogue, which is known to be converted to formycin A 5'-triphosphate in isolated islets, triggers the same sequence of ionic events as that otherwise involved in the process of nutrient-stimulated insulin release and currently attributed to an increase in adenosine 5'-triphosphate (ATP) generation rate. Unexpectedly, formycin A first increased 86Rb outflow, decreased 45Ca outflow and inhibited insulin release from prelabelled islets perifused at physiological or higher concentrations of D-glucose. This early inhibitory effect of formycin A upon insulin release coincided, in perforated patch whole-cell recordings, with an initial transient increase of ATP-sensitive K+ channel activity. A positive secretory response to formycin A, still not associated with any decrease in K+ conductance, was only observed either immediately after formycin A administration to islets already exposed to glibenclamide or during prolonged exposure to the adenosine analogue. This coincided with an increase of cytosolic Ca2+ concentration in intact B-cells and a greater increase of membrane capacitance in response to depolarization in B-cells examined in the perforated patch whole-cell configuration. The latter stimulation of exocytotic activity could not be attributed, however, to any increase in peak or integrated Ca2+ current. Thus, the mode of action of formycin A, or its 5'-triphosphate ester, in islet cells obviously differs from that currently ascribed to endogenous ATP in the process of nutrient-stimulated insulin release.
Lebrun
P
P
Laboratory of Pharmacology, Brussels Free University, 808 Route de Lennik, B-1070 Brussels, Belgium.
Renström
E
E
Antoine
M H
MH
Bokvist
K
K
Holmquist
M
M
Rorsman
P
P
Malaisse
W J
WJ
D000255:Adenosine Triphosphate / Q000096:biosynthesis; D000818:Animals; D002118:Calcium / Q000032:analysis / Q000502:physiology; D015220:Calcium Channels / Q000502:physiology; D002132:Calcium Radioisotopes; D003593:Cytoplasm / Q000737:chemistry; D005089:Exocytosis / Q000187:drug effects; D005573:Formycins / Q000494:pharmacology*; D005905:Glyburide / Q000494:pharmacology; D007328:Insulin / Q000378:metabolism; D007515:Islets of Langerhans / Q000378:metabolism* / Q000648:ultrastructure; D015221:Potassium Channels / Q000187:drug effects / Q000502:physiology; D051381:Rats; D012414:Rubidium Radioisotopes
D015220:Calcium Channels; D002132:Calcium Radioisotopes; D005573:Formycins; D007328:Insulin; D015221:Potassium Channels; D012414:Rubidium Radioisotopes; C034550:formycin; D000255:Adenosine Triphosphate; D005905:Glyburide; D002118:Calcium