Ashkenazi A, Ramachandran J, Capon D J
Department of Molecular Biology, Genentech, Incorporated, South San Francisco, California 94080.
Nature. 1989 Jul 13;340(6229):146-50. doi: 10.1038/340146a0.
Little is known about the factors which regulate the growth and development of the mammalian brain. Although proliferation of neuronal cells ceases relatively early in development, certain types of glial cells proliferate and differentiate mainly perinatally. In the perinatal period, the ability of acetylcholine to stimulate phosphoinositide (PI) hydrolysis in brain reaches peak levels, and indeed the stable acetylcholine analogue carbachol can stimulate PI hydrolysis of primary neonatal astroglial cells. As PI hydrolysis is thought to be important in the regulation of cell proliferation, we investigated whether cellular DNA synthesis can be induced by carbachol. Our results show that carbachol stimulates DNA synthesis via muscarinic acetylcholine receptors (mAChRs), in primary astrocytes derived from perinatal rat brain, in an age-dependent fashion. Carbachol is also mitogenic in certain brain-derived astrocytoma and neuroblastoma cell lines, as well as in chinese hamster ovary (CHO) cells expressing recombinant muscarinic receptors. DNA synthesis is strongly activated by carbachol in those brain-derived cell lines and transfected CHO cells that express mAChR subtypes which activate PI hydrolysis efficiently, and poorly activated in cells expressing mAChR subtypes which only weakly activate PI hydrolysis. These results strongly support a role for acetylcholine in regulating astroglial cell growth in the developing brain, and indicate that the specificity of acetylcholine-induced cell proliferation may be determined by the expression of those mAChR subtypes which activate PI hydrolysis.
关于调节哺乳动物大脑生长和发育的因素，我们所知甚少。虽然神经元细胞的增殖在发育过程中相对较早停止，但某些类型的神经胶质细胞主要在围产期增殖和分化。在围产期，乙酰胆碱刺激大脑中磷酸肌醇（PI）水解的能力达到峰值水平，实际上，稳定的乙酰胆碱类似物卡巴胆碱可以刺激新生原代星形胶质细胞的PI水解。由于PI水解被认为在细胞增殖的调节中很重要，我们研究了卡巴胆碱是否能诱导细胞DNA合成。我们的结果表明，在围产期大鼠脑来源的原代星形胶质细胞中，卡巴胆碱通过毒蕈碱型乙酰胆碱受体（mAChRs）以年龄依赖的方式刺激DNA合成。卡巴胆碱在某些脑源性星形细胞瘤和神经母细胞瘤细胞系以及表达重组毒蕈碱受体的中国仓鼠卵巢（CHO）细胞中也具有促有丝分裂作用。在那些表达能有效激活PI水解的mAChR亚型的脑源性细胞系和转染的CHO细胞中，卡巴胆碱强烈激活DNA合成，而在表达仅微弱激活PI水解的mAChR亚型的细胞中激活作用较弱。这些结果有力地支持了乙酰胆碱在调节发育中大脑星形胶质细胞生长中的作用，并表明乙酰胆碱诱导的细胞增殖的特异性可能由激活PI水解的那些mAChR亚型的表达所决定。
