Role for the Membrane Receptor Guanylyl Cyclase-C in Attenti

中科院武汉物数所徐富强组与NIBS合作,利用多模态的手段和转基因动物,揭示了鸟苷酰环化酶-C(guanylyl cyclase-C,GC-C)的激活,通过cGMP依赖蛋白激酶(PKG),强化由谷氨酸和乙酰胆碱受体导致的多巴胺神经元的兴奋性活动……成果发表在《Science》上。

Role for the Membrane Receptor Guanylyl Cyclase-C in Attention Deficiency and Hyperactive Behavior

Rong Gong,1,2* Cheng Ding,2,3* Ji Hu,2* Yao Lu,2 Fei Liu,4 Elizabeth Mann,5 Fuqiang Xu,4 Mitchell B. Cohen,5 Minmin Luo2,6

1Graduate Program in Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100730, China. 2National Institute of Biological Sciences, Beijing, 102206, China. 3College of Life Sciences, Beijing Normal University, Beijing 100875, China. 4Wuhan Institute of Physics and Mathematics, Chinese Academy of Sciences, Wuhan 430071, China. 5Division of Gastroenterology, Hepatology and Nutrition, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 4522966, USA. 6School of Life Sciences, Tsinghua University, Beijing 100084, China.

*These authors contributed equally to this work.

To whom correspondence should be addressed. E-mail: luominmin@http://doc.guandang.net

Midbrain dopamine neurons regulate many important thought to be expressed principally on intestinal mucosal cells behavioral processes and their dysfunctions are associated (4, 5), is strongly and selectively expressed throughout the with several human neuropsychiatric disorders such as VTA/SNc in mice (6, 7). GC-C mRNA co-localized with Attention Deficit Hyperactivity Disorder (ADHD) and tyrosine hydroxylase (TH) (Fig. 1A-C and figs. S1 and S2), schizophrenia. Here, we report that these neurons in mice an enzyme critical for dopamine synthesis (1). Dual-color selectively express guanylyl cyclase-C (GC-C), a immuostaining revealed that GC-C protein was expressed membrane receptor previously thought to be expressed predominantly on the somata and dendrites of dopaminergic mainly in the intestine. GC-C activation potentiates the neurons in the VTA/SNc (Fig. 1D-I and fig. S1C). The GC-C excitatory responses mediated by glutamate and expression pattern was further confirmed by GC-C acetylcholine receptors via the activity of cGMP-immunostaining in TH-GFP transgenic mice, which express dependent protein kinase (PKG). GC-C knockout mice green fluorescent protein (GFP) in dopamine neurons (fig. exhibit hyperactivity and attention deficits. Moreover, S2A-F) (8). Strong GC-C immunoreactivity was detected in their behavioral phenotypes are reversed by ADHD the GFP+ neurons in the VTA/SNc but not other brain areas therapeutics and a PKG activator. These results indicate (figs. S2G-L and S3).

important behavioral and physiological functions for the GC-C is a membrane receptor for the gut peptide GC-C/PKG signaling pathway within the brain and hormones guanylin (G) and uroguanylin (UG) (9, 10). Upon suggest new therapeutic targets for neuropsychiatric activation it increases the production of intracellular cyclic disorders related to the malfunctions of midbrain guanosine monophosphate (cGMP) and finally opens CFTR dopamine neurons. channels to stimulate electrolyte and water secretion. Its over-Dopamine neurons in the midbrain ventral tegmental area and activation by Escherichia coli heat-stable enterotoxin causes substantia nigra compacta (VTA/SNc) project their axons acute secretory diarrhea (4). Although several membrane GCs extensively to the forebrain and release dopamine to regulate are implicated in behavioral regulations in animals across perse behavioral processes, such as motor activity, taxa (11), the functions of GC-C remain unexplored in the cognition, motivation and learning (1, 2). Numerous nervous system.

dopamine receptor agonists, antagonists, and reuptake As the anatomical organization of the midbrain dopamine inhibitors have been used to treat the symptoms of system appears normal in GC-C knockout (KO) mice (figs. Parkinson's disease, schizophrenia, and ADHD (3). Studying S1D and S4), we examined the physiological functions of how the activity of midbrain dopamine neurons is selectively GC-C signaling. Dopamine neurons in adult mouse brain regulated not only can contribute to our understanding of the slices were recorded using the perforated whole-cell patch-neurobiological mechanisms of behavioral control but also clamp method (fig. S5). Initial recordings revealed no may provide insight into developing more effective obvious effects of GC-C activation that were predicted by treatments of psychiatric disorders. known physiological functions of cGMP-stimulated signaling While studying the functions of membrane guanylyl pathways (12). Applying GC-C ligands G/UG did not affect

cyclases in the nervous system, we observed that GC-C, the intrinsic physiological properties of midbrain dopamine

/ http://doc.guandang.net / 11 August 2011 / Page 1 / 10.1126/science.1207675 Downloaded from http://doc.guandang.net on October 18, 2011

中科院武汉物数所徐富强组与NIBS合作,利用多模态的手段和转基因动物,揭示了鸟苷酰环化酶-C(guanylyl cyclase-C,GC-C)的激活,通过cGMP依赖蛋白激酶(PKG),强化由谷氨酸和乙酰胆碱受体导致的多巴胺神经元的兴奋性活动……成果发表在《Science》上。

neurons (fig. S6). G/UG application also did not produce any activity of GC-C KO mice was more than twice that of wild-effects on the responses carried by AMPA-type glutamate type mice during dark but not light phases after one day in the receptors or GABAA receptors (figs. S7 and S8), suggesting test arena (Figs. 4A and S11A). In a novel open field, these minimal roles of GC-C in directly opening ion channels or mice manifested clear hyperactivity only after they were modulating synaptic responses mediated by ionotropic familiarized with the environment for about 100 minutes (Fig. glutamate or GABA receptors. 4B). The reduction of habituatory effect on locomotion was Unexpectedly, G/UG potentiated the respon …… 此处隐藏：22802字，全部文档内容请下载后查看。喜欢就下载吧 ……