Essential roles of Homer‐1a in homeostatic regulation of pyramidal cell excitability: a possible link to clinical benefits of electroconvulsive shock
Essential roles of Homer‐1a in homeostatic regulation of pyramidal cell excitability: a possible link to clinical benefits of electroconvulsive shock
复制标题
DOI：
10.1111/j.1460-9568.2005.04165.x
复制
发表时间：
2005-06
影响因子：
3.4
通讯作者：
Y. Sakagami;Kenji Yamamoto;S. Sugiura;K. Inokuchi;Takuji Hayashi;N. Kato
中科院分区：
文献类型：
--
作者：
Y. Sakagami;Kenji Yamamoto;S. Sugiura;K. Inokuchi;Takuji Hayashi;N. Kato
Homer‐1a/Vesl1S是支架蛋白家族Homer/Vesl的一员，在癫痫发作时表达，有助于降低癫痫发作的易感性。通过在细胞内注射Homer‐1a蛋白，研究了这种反馈调节的细胞机制。注射降低了膜的兴奋性，表现在两个方面。首先，静息电位超极化5 ~ 10 mV。其次，去极化电流注入诱发的峰值平均频率降低。这种兴奋性的降低可以通过应用以下药物来预防：钙螯合剂BAPTA，钙存储消耗剂环吡唑酸（CPA），肌醇- 1,4,5 -三磷酸受体（IP3R）阻滞剂肝素，磷脂酶C （PLC）抑制剂U - 73122，代谢性谷氨酸受体（mGluR）拮抗剂2 -甲基- 6 -（苯乙基）吡啶（MPEP）和大电导钙活化钾通道（BK通道）拮抗剂charybdotoxin。小电导钙活化钾通道（SK通道）阻滞剂去qualinium无效。这些发现表明，Homer‐1a激活mGluR产生IP3， IP3引起肌醇诱导的钙释放和随后的BK通道打开，从而使注射的神经元超极化。在电惊厥休克（ECS）大鼠的切片中，在没有注射Homer‐1a的情况下观察到类似的兴奋性降低。ECS诱导的兴奋性降低被MPEP、白肉毒素、肝素或BAPTA所消除。细胞内注射抗Homer‐1a抗体也有抑制作用，但抗Homer‐1b/c抗体无抑制作用。我们提出，ECS诱导的Homer‐1a刺激了与注入的Homer‐1a相同的通路，从而驱动了兴奋性的反馈调节。
Homer‐1a/Vesl1S, a member of the scaffold protein family Homer/Vesl, is expressed during seizure and serves to reduce seizure susceptibility. Cellular mechanisms for this feedback regulation were studied in neocortex pyramidal cells by injecting Homer‐1a protein intracellularly. The injection reduced membrane excitability as demonstrated in two ways. First, the resting potential was hyperpolarized by 5–10 mV. Second, the mean frequency of spikes evoked by depolarizing current injection was decreased. This reduction of excitability was prevented by applying each of the followings: the calcium chelator BAPTA, the calcium store depletor cyclopiazonic acid (CPA), the insitol‐1,4,5‐trisphosphate receptor (IP3R) blocker heparin, the phospholipase C (PLC) inhibitor U‐73122, the metabotropic glutamate receptor (mGluR) antagonist 2‐methyl‐6‐(phenylethynyl)‐pyridine (MPEP), and the large‐conductance calcium activated potassium channel (BK channel) antagonist charybdotoxin. The small‐conductance calcium activated potassium channel (SK channel) blocker dequalinium was ineffective. These findings suggest that activation of mGluR by Homer‐1a produced IP3, which caused inositol‐induced calcium release and a consequent BK channel opening, thus hyperpolarizing the injected neurons. In slices from rats subjected to electroconvulsive shock (ECS), a comparable reduction of excitability was observed without Homer‐1a injection. The ECS‐induced reduction of excitability was abolished by MPEP, charybdotoxin, heparin or BAPTA. Intracellular injection of anti‐Homer‐1a antibody was suppressive as well, but anti‐Homer‐1b/c antibody was not. We propose that ECS‐induced Homer‐1a stimulated the same pathway as did the injected Homer‐1a, thereby driving a feedback regulation of excitability.