A schizophrenia-linked mutation in PIP5K2A fails to activate neuronal M channels

RATIONALE: Evidence for an association between phosphatidylinositol-4-phosphate 5-kinase II alpha (PIP5K2A) and schizophrenia was recently obtained and replicated in several samples. PIP5K2A controls the function of KCNQ channels via phosphatidylinositol-4,5-bisphosphate (PIP2) synthesis. Interestingly, recent data suggest that KCNQ channels suppress basal activity of dopaminergic neurons and dopaminergic firing. Activation of KCNQ accordingly attenuates the central stimulating effects of dopamine, cocaine, methylphenidate, and phenylcyclidine. OBJECTIVE: The aim of this study was to explore the functional relevance of PIP5K2A, which might influence schizophrenic behavior. MATERIALS AND METHODS: Here, we study the effects of the neuronal PIP5K2A on KCNQ2, KCNQ5, KCNQ2/KCNQ3, and KCNQ3/KCNQ5 in the Xenopus expression system. RESULTS: We find that wild-type PIP5K2A but not the schizophrenia-associated mutant (N251S)-PIP5K2A activates heteromeric KCNQ2/KCNQ3 and KCNQ3/KCNQ5, the molecular correlate of neuronal M channels. Homomeric KCNQ2 and KCNQ5 channels were not activated by the kinase indicating that the presence of KCNQ3 in the channel complex is required for the kinase-mediated effects. Acute application of PI(4,5)P2 and a PIP2 scavenger indicates that the mutation N251S renders the kinase PIP5K2A inactive. CONCLUSIONS: Our results suggest that the schizophrenia-linked mutation of the kinase results in reduced KCNQ channel function and thereby might explain the loss of dopaminergic control in schizophrenic patients. Moreover, the addictive potential of dopaminergic drugs often observed in schizophrenic patients might be explained by this mechanism. At least, the insufficiency of (N251S)-PIP5K2A to stimulate neuronal M channels may contribute to the clinical phenotype of schizophrenia.     

Blockade of HERG channels expressed in Xenopus oocytes by external H+

 We have investigated the effect of external H⁺ concentration ([H⁺]_o)on the human-ether-a-go-go-related gene (HERG) current (I _HERG), the molecular equivalent of the cardiac delayed rectifier potassium current (I _Kr), expressed in Xenopus oocytes, using the two-microelectrode voltage-clamp technique. When [H⁺]_o was increased, the amplitude of the I _HERG elicited by depolarization decreased, and the rate of current decay on repolarization was accelerated. The activation curve shifted to a more positive potential at lower external pH (pH_o) values (the potential required for half-maximum activation, V _1/2, was: –41.8 mV, –38.0 mV, –33.7 mV, –26.7 mV in pH_o 8.0, 7.0, 6.6, 6.2, respectively). The maximum conductance (g _max) was also affected by [H⁺]_o: a reduction of 7.9%, 14.6%, and 22.8% was effected by decreasing pH_o from 8.0 to 7.0, 6.6, and 6.2, respectively. We then tested whether this pH effect was affected by the external Ca²⁺ concentration, which is also known to block HERG channels. When the extracellular Ca²⁺ concentration was increased from 0.5 mM to 5 mM, the shift in V _1/2 caused by increasing [H⁺]_o was attenuated, suggesting that these two ions compete for the same binding site. On the other hand, the decrease in g _max caused by increasing [H⁺]_o was not significantly affected by changing external Ca²⁺ levels. The results indicate that HERG channels are inhibited by [H⁺]_o by two different mechanisms: voltage-dependent blockade (shift of V _1/2) and the decrease in g _max. With respect to the voltage-dependent blockade, the interaction between H⁺ and Ca²⁺ is competitive, whereas for the decreasing g _max, their interaction is non-competitive. Received: 12 January 1999 / Received after revision: 15 February 1999 / Accepted: 16 February 1999     

督脉刺法治疗脑血管性痴呆的临床研究

目的观察督脉刺法治疗血管性痴呆的临床疗效。方法将85例血管性痴呆患者随机分为2组:治疗组用针刺加哈伯因治疗,对照组仅用哈伯因治疗,治疗前后用简易智能量表(MMSE)、日常生活能力量表(ADL)进行评分。结果2组治疗后MMSE积分、ADL积分均明显提高,且治疗组提高程度优于对照组。结论督脉刺法能显著改善血管性痴呆患者的认知功能及日常生活能力,临床疗效显著。     

针刺足阳明经穴对大鼠胃运动影响及其与P物质的关系

为了探讨针刺足阳明经穴有运动的调整作用是否与脑肠肽中的Ｐ物质（ＳＰ）有关。以乙醇灌胃造成大鼠胃粘膜损伤模型,气囊法测量胃运动频率和波幅的变化率,采用放免分析法（ＲＩＡ）检测大鼠胃窦及延髓ＳＰ含量。结果显示：模型组胃运动频率和波幅呈抑制状态,胃窦ＳＰ含量降低,延髓ＳＰ含量升高;针刺四白、天枢、足三里穴可促进胃运动恢复,且天枢、足三里组胃ＳＰ含量升高,延髓ＳＰ含量呈下降趋势,针刺非穴组对胃运动和ＳＰ影     

养正消积胶囊配合介入化疗治疗原发性肝癌随机双盲多中心临床研究

目的：观察养正消积胶囊对原发性肝癌介入化疗术后患者的疗效和安全性。方法：采用随机双盲、安慰剂对照,利用SAS统计软件将604例病例分成治疗组402例和对照组202例,2组均采用化学疗法,治疗组加服养正消积胶囊,1次4粒,3次/d,饭后30min温开水送服,对照组加服安慰剂,观察比较两组实体肿瘤疗效及中医证候、生存质量、体重、免疫功能等相关指标的变化。疗程为4周。结果：实体肿瘤的疗效,治疗组缓解率22.4%,对照组15.3%,两组比较,差异有统计学意义（P〈0.01）。中医症状和体征疗效,治疗组总有效率为65.2%,对照组总有效率36.1%,两组比较,差异有统计学意义（P〈0.01）。生存质量疗效,治疗组升高稳定率为85.0%,对照组升高稳定率为76.7%,两组比较,差异有统计学意义（P〈0.01）。体重疗效,治疗组升高稳定率为78.3%,对照组升高稳定率为70.8%,两组比较,差异有统计学意义（P〈0.01）。免疫学指标变化比较,治疗组治疗前后无明显变化,NK细胞均数比较,对照组治疗前后差异有统计学意义（P〈0.05）。结论：养正消积胶囊对介入化疗术后原发性肝癌安全,有效。     

中药归经

中药归经的概念源自《黄帝内经》,是中医药理论的重要组成部分。药物所治病证的经络和脏腑归属为中药归经理论的临床依据,而药物的五味特性是中药归经的理论依据,二者互参构成了中药的归经理论。随着现代科学的不断发展,近年来,众多研究从药物化学、药代动力学等角度进行的体内、体外实验研究,证实一些中药的有效成分分布与其归经一致,其临床治疗作用也与其归经的效用内涵一致,验证了中药归经理论的科学性。在临床实际应用中,归经理论作为重要的中医药理论,对于临床根据辩证辨病结果组方、选药有着重要的指导意义。此外,对于精确地选用适宜的药味和炮制规格,归经等中医药传统认识也是重要的理论依据。     

酪氨酸的磷酸化及去磷酸化对心脏钾离子通道的调控

心脏钾离子通道是人体内广泛存在的、种类最多、作用最复杂的一类离子通道,并在人类心肌细胞动作电位的各个时程中发挥着重要的作用。近年来由于新兴技术如膜片钳技术、基因突变技术、分子克隆技术等诸多技术的运用和发展,人们对钾离子通道的基因表达、分子结构、生理病理作用及调控机制等方面都有了很深的认识,然而对蛋白磷酸化与去磷酸化对心脏钾离子通道的调控尤其是酪氨酸磷酸化和去磷酸化调控方面的研究却比较少,为此做一简单综述。     

Localization of Cystic Fibrosis Transmembrane Conductance Regulator in Epithelial Cells of Nasal Polyps and Postoperative Polypoid Mucosae

Cystic fibrosis transmembrane conductance regulator (CFTR) is a chloride channel protein that plays an important role in electrolyte and water transport through the respiratory epithelial cells. In order to understand the possible role of CFTR in the pathogenesis of nasal polyps and postoperative polypoid mucosae, we aimed to characterize the localization of CFTR in the epithelia of nasal polyps and postoperative polypoid mucosae of subjects who did not manifest the phenotypic expression of cystic fibrosis. Immunohistochemical staining for CFTR, using monoclonal mouse anti-human CFTR, was performed on tissue sections of 4 normal turbinates and nasal polyps and postoperative polypoid mucosae from 10 patients who underwent endoscopic intranasal operations. CFTR showed a typical apical distribution in the normal turbinate mucosae whereas, in the nasal polyps, CFTR demonstrated a heterogenous pattern of localization comprising diffuse or scattered cytoplasmic labelling, very low to undetectable labelling, intense perinuclear staining and intermingled typical apical location. In postoperative polypoid mucosae, the pattern of CFTR localization was less heterogeneous than in the nasal polyp epithelial cells and showed a more prominent feature of diffuse cytoplasmic staining. These results suggest that an altered localization of the CFTR may have a role in the pathogenesis of nasal polyps and postoperative polypoid mucosa.