Neve R L, Coopersmith R, McPhie D L, Santeufemio C, Pratt K G, Murphy C J, Lynn S D
Department of Genetics, Harvard Medical School, Boston, Massachusetts 02115, USA.
J Neurosci. 1998 Oct 1;18(19):7757-67. doi: 10.1523/JNEUROSCI.18-19-07757.1998.
Structural plasticity of nerve cells is a requirement for activity-dependent changes in the brain. The growth-associated protein GAP-43 is thought to be one determinant of such plasticity, although the molecular mechanism by which it mediates dynamic structural alterations at the synapse is not known. GAP-43 is bound by calmodulin when Ca2+ levels are low, and releases the calmodulin when Ca2+ levels rise, suggesting that calmodulin may act as a negative regulator of GAP-43 during periods of low activity in the neurons. To identify the function of GAP-43 during activity-dependent increases in Ca2+ levels, when it is not bound to calmodulin, we sought proteins with which GAP-43 interacts in the presence of Ca2+. We show here that rabaptin-5, an effector of the small GTPase Rab5 that mediates membrane fusion in endocytosis, is one such protein. We demonstrate that GAP-43 regulates endocytosis and synaptic vesicle recycling. Modulation of endocytosis by GAP-43, in association with rabaptin-5, may constitute a common molecular mechanism by which GAP-43 regulates membrane dynamics during its known roles in activity-dependent neurotransmitter release and neurite outgrowth.
神经细胞的结构可塑性是大脑中依赖活动的变化所必需的。生长相关蛋白GAP - 43被认为是这种可塑性的一个决定因素，尽管其介导突触处动态结构改变的分子机制尚不清楚。当Ca2 +水平较低时，GAP - 43与钙调蛋白结合，而当Ca2 +水平升高时，GAP - 43会释放钙调蛋白，这表明在神经元活动较低的时期，钙调蛋白可能作为GAP - 43的负调节因子。为了确定在依赖活动的Ca2 +水平升高期间（此时GAP - 43不与钙调蛋白结合）GAP - 43的功能，我们寻找了在Ca2 +存在时与GAP - 43相互作用的蛋白质。我们在此表明，rabaptin - 5是小GTP酶Rab5的效应器，介导内吞作用中的膜融合，它就是这样一种蛋白质。我们证明GAP - 43调节内吞作用和突触小泡循环。GAP - 43与rabaptin - 5一起对内吞作用的调节，可能构成一种常见的分子机制，通过这种机制，GAP - 43在其已知的依赖活动的神经递质释放和神经突生长作用中调节膜动力学。
