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FUNCTIONAL OF CaィイD12+ィエD1-Calmodulin sensitive a denylate cyclase in central neurons

CaD12+D1-钙调蛋白对中枢神经元否认环化酶敏感的功能

基本信息

批准号：
10470009
负责人：
AKAIKE Norio
金额：
$ 6.85万
依托单位：
KYUSHU UNIVERSITY
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B)
财政年份：
1998
资助国家：
日本
起止时间：
1998 至 1999
项目状态：
已结题

项目摘要

To explore the intracellular pathways activated by vasopressin receptors, the effects of arginine vasopressin (AVP) and its analogs mediating glycine (Gly)-induced Cl- currents (lィイD2GlyィエD2) were examined in acutely dissociated rat hoppocampal CA1 neurons using the while-cell patch recording technique. AVP and its analogs inhibited lィイD2GlyィエD2 in a concentration-dependent manner. The inhibitory actions of AVP (4-9) [AVP metabolite] and NC-1900 [AVP (4-9) analog] were reversed by a VィイD21ィエD2 receptor antagonist, or pretreatment with BAPTA-AM. In contrast, these blocking procedures had no effect on the DDAVP [VィイD22ィエD2 agonist] action. A VィイD22ィエD2 receptor antagonist did not block the inhibitory action of AVP(4-9) or NC-1900, but blocked that of DDAVP. The inhibitory action of AVP was completely blocked by the co-application of the VィイD21ィエD2 and VィイD22ィエD2 antagonists. The inhibitory action of NC-1900 was not affected by perfusion with a CaィイD12+ィエD1-free external solution, but was strongly blocked by thapsigargin. The intercellular application of heparin of anti-IPィイD23ィエD2 also blocked the NC-1900 action. Furthermore, CaィイD12+ィエD1/calmodulin (CaM) inhibitors blocked the NC-1900 action, while a Cam-dependent kinase II inhibitor and PKC modulators had no effect. 2', 5'-Dideoxyadenosine, an adenylate cyclase inhibitor, H-89 and Rp-cAMPS blocked the inhibitory actions of NC-1900 and DDAVP. These results suggest that the activation of the VィイD21ィエD2 receptor in the hippocampal neurons induces the production of IPィイD23ィエD2 which releases CaィイD12+ィエD1 from the IPィイD23ィエD2-sensitive CaィイD12+ィエD1 storage sites. The CaィイD12+ィエD1 binds to CaM, resulting in the activation of CaィイD12+ィエD1/CaM-sensitive adenylate cyclases. The activation of PKA through the adenylate cyclase inhibits lィイD2GlyィエD2.

为探讨加压素受体激活的细胞内通路，采用全细胞膜片钳记录技术，观察了精氨酸加压素（AVP）及其类似物对甘氨酸（Gly）诱导的大鼠海马CA 1区神经元Cl-电流（1-D2 Gly-D2）的影响。AVP及其类似物以浓度依赖性方式抑制谷氨酸D2 Gly谷氨酸D2。AVP（4-9）[AVP代谢物]和NC-1900 [AVP（4-9）类似物]的抑制作用可被V_（21）D_2受体拮抗剂或BAPTA-AM预处理逆转。相反，这些阻断程序对DDAVP [V β D22受体D2激动剂]的作用没有影响。V_（22）D_2受体拮抗剂不能阻断AVP（4-9）或NC-1900的抑制作用，但能阻断DDAVP的抑制作用。AVP的抑制作用可被V β D21受体D2和V β D22受体D2受体拮抗剂联合应用完全阻断。NC-1900的抑制作用不受灌流与Ca ~（2+）D_12 + Ca ~（2+）D_1-free外部溶液的影响，但被毒胡萝卜素强烈阻断。细胞间应用抗IP抗体D23的肝素D2也阻断了NC-1900的作用。此外，钙调素D12+钙调素D1/钙调素（CaM）抑制剂阻断NC-1900的作用，而CAM依赖性激酶II抑制剂和PKC调节剂没有影响。腺苷酸环化酶抑制剂2 '，5'-二脱氧腺苷、H-89和Rp-cAMPS可阻断NC-1900和DDAVP的抑制作用。这些结果表明，激活海马神经元中的V β D21 β D2受体诱导产生IP β D23 β D2，其从IP β D23 β D2敏感的Ca β D12 + Ca β D1储存位点释放Ca β D12 + Ca β D1。Ca ~（2+）D12+ Ca ~（2+）D1与CaM结合，导致Ca ~（2+）D12+ Ca ~（2+）D1/CaM敏感性腺苷酸环化酶的激活。PKA通过腺苷酸环化酶的激活抑制腺苷酸D2 Gly腺苷酸D2。