Mice homozygous for the L250T mutation in the α7 nicotinic acetylcholine receptor show increased neuronal apoptosis and die within 1 day of birth
Mice homozygous for the L250T mutation in the α7 nicotinic acetylcholine receptor show increased neuronal apoptosis and die within 1 day of birth
复制标题
DOI：
10.1046/j.1471-4159.2000.0742154.x
复制
发表时间：
2000-05-01
影响因子：
4.7
通讯作者：
Patrick, JW
中科院分区：
文献类型：
--
作者：
Orr-Urtreger, A;Broide, RS;Patrick, JW
α 7烟碱乙酰胆碱受体（nAChR）参与调节神经递质的释放，并可能在调节神经元生长和分化中发挥作用。在鸡α 7 nAChR的通道结构域中，亮氨酸247被苏氨酸取代，这增加了激动剂亲和力并降低了脱敏速率，从而为该受体创建了“功能获得”模型。我们已经产生了小鼠表达类似的突变（L250 T）在α 7 nAChR使用同源重组技术，并在这里报告其特点。与野生型同窝仔相比，L250 T突变杂合子（+/T）小鼠存活、可育且解剖学正常。相比之下，纯合子（T/T）L250 T小鼠在出生后2-24小时内死亡。T/T小鼠幼仔的脑表现出α 7 nAChR蛋白水平的显著降低，并在整个躯体感觉皮层中表现出广泛的凋亡细胞死亡。此外，α 7 L250 T nAChR在T/T新生小鼠脑内的神经元上功能性表达，并且具有与在卵母细胞中表达的大鼠α 7 L250 T和鸡α 7 L247 T突变nAChR所观察到的那些一致的性质。这些发现表明，在发育中的脑中仅表达α 7 L250 T突变nAChR的神经元对异常凋亡敏感，这可能是由于。增加Ca 2+流入。
The alpha 7 nicotinic acetylcholine receptor (nAChR) has been implicated in modulating neurotransmitter release and may play a role in the regulation of neuronal growth and differentiation. A threonine for leucine 247 substitution in the channel domain of the chick alpha 7 nAChR increases agonist affinity and decreases the rate of desensitization, creating a "gain of function" model for this receptor. We have generated mice that express the analogous mutation (L250T) in the alpha 7 nAChR using the techniques of homologous recombination and here report their characteristics. Mice heterozygous (+/T) for the L250T mutation are viable, fertile, and anatomically normal compared with wild-type littermates. In contrast, homozygous (T/T) L250T mice die within 2-24 h of birth. Brains of T/T mouse pups exhibit a marked reduction in alpha 7 nAChR protein levels and show extensive apoptotic cell death throughout the somatosensory cortex. Furthermore, alpha 7 L250T nAChRs are functionally expressed on neurons within the brains of T/T neonatal mice and have properties that are consistent with those observed for the rat alpha 7 L250T and the chick alpha 7 L247T mutant nAChRs expressed in oocytes. These findings indicate that neurons in the developing brain expressing only alpha 7 L250T mutant nAChRs are susceptible to abnormal apoptosis, possibly due. to increased Ca2+ influx.