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Greengard遗产：留给后人新的领域去拓展，科学奖与传承

纵观历史长流，科学的发展是由众多很小的发现逐渐累积的。但在这所有的发现中，最重要的是那些突破性的、开启新领域的发现。经济学上有个说法叫帕累托法则（Pareto principle，俗称二八法则），即80%的土地为20%富人所有。科学上也有类似的现象，即80%的大文章由20%的精英科学家发表。在诺贝尔奖获得者中该比例更高。当然，这也会进入一个“富人越来越富”的循环。精英科学家获得更多的资助、招募更优秀的学生、发表更多的文章，这是科学上的马太效应（Matthew Effect in Science）。

神经传递慢反应的“慢”是相对神经传递快反应而言的。从神经递质（如谷氨酸）结合离子型受体，通道打开，离子跨膜传输形成电流，细胞电压变化，整个反应发生在1毫秒之内；而由代谢型受体（比如多巴胺受体）介导的慢反应则耗时几百毫秒，甚至几分钟。但对于化学反应而言，几百毫秒到几分钟的“慢”反应仍然是很“快”的反应，故一开始Greengard的同行都不接受他的观点。

但Greengard的研究为我们开启了全新的一个世界，让我们认识到这个“慢”的磷酸化／去磷酸化反应下游的多个效应物，包括：

1）离子通道，通过磷酸化修饰改变离子通道传输离子的能力，从而影响电导（G，电阻的倒立1/R，通道打开，电阻下降，电导上升）和动作电位（参考上文）；

2）离子泵，在动作电位时，离子顺着细胞内外浓度差传输之后，需要通过离子泵逆浓度差传输回去，恢复浓度差，而对离子泵的磷酸化修饰则可通过改变离子浓度来影响细胞活性；

3）神经递质受体，包括离子型和代谢型受体（快和慢神经传递都受影响），对受体的磷酸化修饰可以一方面直接影响受体活性，另一方面影响受体插入细胞膜和从细胞膜内吞，从而改变受体的多少，两个影响都可改变突触的强弱，即突触可塑性；

4）基因表达，包括对神经递质受体基因表达的影响，从而影响受体的多少。

在调控突触可塑性方面，改变受体活性的影响较快，受体的入膜和内吞的影响较慢持续时间较长，受体基因表达的影响最慢持续时间最长。突触可塑性目前认为是学习和记忆的基础，Greengard 的好友Eric Kandel在这方面有重大贡献。总之，基本上这里提到的每一个研究都是开创一个新的领域。

最终Greengard与发现多巴胺的Carlsson、研究学习和记忆的神经分子机制的Kandel共享了2000年诺贝尔生理学或医学奖。2004年，Greengard将他的诺奖奖金用于成立Pearl Meister Greengard Prize，纪念他因难产而死的母亲。Greengard直到上大学才知道他生母的事情，对于生母Pearl Meister Greengard，他没有任何记忆、照片和信息，他希望这个奖能够证明他母亲的存在。

该奖由洛克菲勒大学每年一次颁发给女性生物学家，用来支持女性科学家。获奖者中已有三人后来获诺贝尔奖，包括去年因CRISPR技术而获诺贝尔化学奖的Jennifer Doudna。获奖者中还有中科大天才班毕业生、著名华人生物物理学家庄小威。今年10月1日，mRNA疫苗技术发明人之一Katalin Karikó也被授予该奖。

Greengard的小儿子Leslie有医学和计算机科学双博士学位，两人曾合作建立多巴胺信号通路数学模型59。

未完待续

现在我们知道多巴胺受体是G蛋白偶联的受体GPCR，一类结合多巴胺后激活神经细胞（一型受体），另一类结合多巴胺后抑制神经细胞（二型受体）。我们也知道纹状体SPN细胞有两条投射通路，一条直接通路促进运动（Go），另一条间接通路抑制运动（NoGo）。那么多巴胺一型／二型受体和直接／间接通路又有什么关系呢，多巴胺如何通过影响直接／间接通路来调控运动？颜震做的研究是什么呢？我们下回分解。

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