Sweatt J D, Volterra A, Edmonds B, Karl K A, Siegelbaum S A, Kandel E R
Howard Hughes Medical Institute, College of Physicians and Surgeons, Columbia University, New York, New York 10032.
Nature. 1989 Nov 16;342(6247):275-8. doi: 10.1038/342275a0.
Neurotransmitter can modulate neuronal activity through a variety of second messengers that act on ion channels and other substrate proteins. The most commonly described effector mechanism for second messengers in neurons depends on protein phosphorylation mediated by one of three sets of kinases: the cyclic AMP-dependent protein kinases, the Ca2+-calmodulin-dependent protein kinases, and the Ca2+-phospholipid-dependent protein kinases. In addition, some neurotransmitters and second messengers can also inhibit protein phosphorylation by lowering cAMP levels (either by inhibiting adenylyl cyclase or activating phosphodiesterases). This raises the question: can neurotransmitters also modulate neuronal activity by decreasing protein phosphorylation that is independent of cAMP? Various biochemical experiments show that a decrease in protein phosphorylation can arise through activation of a phosphatase or inhibition of kinases. In none of these cases, however, is the physiological role for the decrease in protein phosphorylation known. Here we report that in Aplysia sensory neurons, the presynaptic inhibitory transmitter FMRFamide decreases the resting levels of protein phosphorylation without altering the level of cAMP. Furthermore, FMRFamide overrides the cAMP-mediated enhancement of transmitter release produced by 5-hydroxytryptamine (5-HT), and concomitantly reverses the cAMP-dependent increase in protein phosphorylation produced by 5-HT. These findings indicate that a receptor-mediated decrease in protein phosphorylation may play an important part in the modulation of neurotransmitter release.
神经递质可通过多种作用于离子通道和其他底物蛋白的第二信使来调节神经元活动。神经元中最常描述的第二信使效应机制依赖于由三组激酶之一介导的蛋白磷酸化：环磷酸腺苷依赖性蛋白激酶、钙调蛋白依赖性蛋白激酶和钙磷脂依赖性蛋白激酶。此外，一些神经递质和第二信使还可通过降低环磷酸腺苷水平（通过抑制腺苷酸环化酶或激活磷酸二酯酶）来抑制蛋白磷酸化。这就提出了一个问题：神经递质是否也能通过独立于环磷酸腺苷的蛋白磷酸化减少来调节神经元活动？各种生化实验表明，蛋白磷酸化的减少可通过磷酸酶的激活或激酶的抑制而产生。然而，在这些情况下，蛋白磷酸化减少的生理作用均不明确。在此我们报道，在海兔感觉神经元中，突触前抑制性递质FMRF酰胺降低了蛋白磷酸化的静息水平，而不改变环磷酸腺苷水平。此外，FMRF酰胺可抵消5-羟色胺（5-HT）产生的环磷酸腺苷介导的递质释放增强作用，并同时逆转5-HT产生的环磷酸腺苷依赖性蛋白磷酸化增加。这些发现表明，受体介导的蛋白磷酸化减少可能在神经递质释放的调节中起重要作用。
