VOLTAGE-DEPENDENT NA-ISLET BETA-CELLS - EVIDENCE FOR ROLES IN THE GENERATION OF ACTION-POTENTIALS AND INSULIN-SECRETION( AND CA2+ CURRENTS IN HUMAN PANCREATIC)

We describe three voltage-dependent inward currents in human pancreati c beta-cells. First, a rapidly inactivating Na+ current, blocked by te trodotoxin (TTX) is seen upon brief depolarization to or beyond -40 mV . Second, a transient, low-voltage-activated (LVA), amiloride-blockabl e Ca2+ current is seen upon depolarization to or beyond -55 mV; it ina ctivates within less than Is of sustained depolarization to -40 mV. Th ird, a more sustained, high-voltage-activated (HVA) Ca2+ current, whic h shows variable sensitivity to dihydropyridines is seen upon depolari zation to or beyond -40 mV, and thereafter slowly inactivates over a t ime course of many seconds. Our pharmacological evidence suggests that all three currents contribute to action potential initiation and upst roke when the background membrane potential (V-m) is equal or negative to -45 to -40 mV, a situation often induced by glucose concentrations (5-6 mM) in the range of those seen post-prandially. Consistent with this, TTX drastically reduces both transient and sustained insulin sec retion in the presence of 5-6 mM glucose, but has little effect in 10 mM glucose, at which concentration cells rapidly depolarize to approxi mate to-35 mV, a V-m sufficient to rapidly inactivate Na+ and LVA Ca2 currents.