Wollheim C B, Blondel B, Renold A E, Sharp G W
Diabetologia. 1976 Jul;12(3):269-77. doi: 10.1007/BF00422095.
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 arginine-stimulated 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.
在含有2.5 mM钙离子的培养基中，对新生大鼠胰腺单层培养物中胰高血糖素的释放进行了4小时的测量，观察到了与环磷酸腺苷（cAMP）相关的显著释放抑制。无论细胞内环磷酸腺苷水平是通过添加外源性环磷酸腺苷或二丁酰环磷酸腺苷、用茶碱抑制磷酸二酯酶，还是用霍乱毒素刺激腺苷酸环化酶而升高，均观察到这种抑制作用。这种抑制作用对环磷酸腺苷具有浓度依赖性，添加腺苷一磷酸（AMP）、二磷酸腺苷（ADP）或三磷酸腺苷（ATP）无法重现该抑制作用。腺苷也抑制胰高血糖素的释放，而ATP具有刺激作用。从时间进程研究来看，在孵育两小时后，环磷酸腺苷和霍乱毒素的抑制作用呈进行性。使用霍乱毒素时，观察到胰高血糖素释放有早期刺激作用。环磷酸腺苷和霍乱毒素对精氨酸刺激的胰高血糖素释放的影响是在孵育的第一小时进一步刺激胰高血糖素释放。因此，提高细胞内环磷酸腺苷水平的作用是双相的，即观察到了对胰高血糖素释放的早期刺激和晚期抑制。在研究这些反应的性质时，发现钙离子具有显著的控制作用：在钙离子浓度为0.3 mM及更低时，未发现环磷酸腺苷对胰高血糖素释放有影响。培养基中钙离子浓度为1 mM时，环磷酸腺苷在早期（30分钟）刺激胰高血糖素释放，此后不再有进一步影响。在存在2.5 mM钙离子的情况下，环磷酸腺苷不会早期刺激，但会导致释放的延迟抑制。结论是，环磷酸腺苷对胰高血糖素释放的作用可以是刺激性的或抑制性的，这取决于培养基中的钙离子浓度以及暴露于升高的环磷酸腺苷水平的持续时间。
