Davies Andrew G, Bettinger Jill C, Thiele Tod R, Judy Meredith E, McIntire Steven L
Ernest Gallo Clinic and Research Center, Department of Neurology, Programs in Neuroscience and Biomedical Science, University of California, San Francisco, 5858 Horton Street, Suite 200, Emeryville, California 94608, USA.
Neuron. 2004 Jun 10;42(5):731-43. doi: 10.1016/j.neuron.2004.05.004.
Variation in the acute response to ethanol between individuals has a significant impact on determining susceptibility to alcoholism. The degree to which genetics contributes to this variation is of great interest. Here we show that allelic variation that alters the functional level of NPR-1, a neuropeptide Y (NPY) receptor-like protein, can account for natural variation in the acute response to ethanol in wild strains of Caenorhabditis elegans. NPR-1 negatively regulates the development of acute tolerance to ethanol, a neuroadaptive process that compensates for effects of ethanol. Furthermore, dynamic changes in the NPR-1 pathway provide a mechanism for ethanol tolerance in C. elegans. This suggests an explanation for the conserved function of NPY-related pathways in ethanol responses across diverse species. Moreover, these data indicate that genetic variation in the level of NPR-1 function determines much of the phenotypic variation in adaptive behavioral responses to ethanol that are observed in natural populations.
个体对乙醇急性反应的差异对确定酒精中毒易感性有重大影响。遗传学对这种差异的贡献程度备受关注。在此我们表明，改变神经肽Y（NPY）受体样蛋白NPR-1功能水平的等位基因变异，可以解释秀丽隐杆线虫野生菌株对乙醇急性反应的自然变异。NPR-1负向调节对乙醇急性耐受性的发展，急性耐受性是一种补偿乙醇作用的神经适应性过程。此外，NPR-1信号通路的动态变化为秀丽隐杆线虫的乙醇耐受性提供了一种机制。这为跨物种乙醇反应中NPY相关信号通路的保守功能提供了解释。此外，这些数据表明，NPR-1功能水平的遗传变异决定了自然种群中观察到的对乙醇适应性行为反应的大部分表型变异。
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