Stimulatory and inhibitory effects of cyclic AMP on pancreatic glucagon release from monolayer cultures and the controlling role of calcium

Abstract

Summary. When glucagon release from monolayer cultures of newborn rat pancreas was measured over four hours in media containing 2.5 mM Ca + +, a significant cyclic AMP-related inhibition of release was observed. This was noted whether intracellular cyclic AMP levels were raised by the addition of exogenous cyclic AMP or dibutyryl cyclic AMP, by phosphodiesterase inhibition with theophylline, or by the stimulation of adenylate cyclase with cholera toxin. The inhibition was concentration dependent for cyclic AMP and could not be reproduced by the addition of AMP, ADP or ATP. Adenosine also inhibited glucagon release while ATP was stimulatory. From time course studies it appeared that the inhibitory effects of cyclic AMP and cholera toxin were progressive after two hours of incubation. With cholera toxin an early stimulation of glucagon release was observed. The effects of cyclic AMP and cholera toxin on argininestimulated glucagon release were to stimulate further the glucagon release during the first hour of the incubation. Thus, the effects of raising intracellular cyclic AMP levels were biphasic in that both an early stimulation and a late inhibition of glucagon release were observed. In examining the nature of these responses a remarkable controlling role for Ca ++ was uncovered: at Ca + + concentrations of 0.3 mM and lower no effect of cyclic AMP on glucagon release was found. With 1 mM Ca ++ in the medium cyclic AMP stimulated glucagon release early (30 min) and thereafter had no further effect. In the presence of 2.5 mM Ca + + cyclic AMP did not stimulate early but did cause the delayed inhibition of release. It is concluded that the effect of cyclic AMP on glucagon release can be either stimulatory or inhibitory depending upon the Ca + + concentration of the medium and the duration of exposure to raised cyclic AMP levels.

Palmitate Stimulation of Glucagon Secretion in Mouse Pancreatic α-Cells Results From Activation of l-Type Calcium Channels and Elevation of Cytoplasmic Calcium

“…Palmitate increases ␣-cell Ca 2؉ currents. Glucagon secretion is a Ca 2ϩ -dependent process mediated by Ca 2ϩ influx through voltage-gated Ca 2ϩ channels (27)(28)(29). We first measured whole-cell Ca 2ϩ currents using Ba 2ϩ as the charge carrier during depolarizations from a holding potential of Ϫ70 mV to membrane potentials between Ϫ50 and ϩ60 mV before and after addition of 0.5 mmol/l palmitate (Fig.…”