Yamamoto Kenji, Sakagami Yu, Sugiura Shigeki, Inokuchi Kaoru, Shimohama Shun, Kato Nobuo
Department of Integrative Brain Science, Kyoto University Graduate School of Medicine, Kyoto 606-8501, Japan.
Eur J Neurosci. 2005 Sep;22(6):1338-48. doi: 10.1111/j.1460-9568.2005.04278.x.
The scaffold protein family Homer/Vesl serves to couple surface receptors or channels with endoplasmic calcium release channels. Homer 1a/Vesl-1S is regarded as regulating such coupling in an activity-dependent manner. The present calcium photometry and electrophysiological measurement revealed that Homer 1a up-regulates voltage-dependent calcium channels (VDCCs), depending on inositol-1,4,5-trisphosphate (IP3) receptors (IP3Rs). In rat neocortex pyramidal cells, intracellular injection by diffusion from the patch pipette (referred to as 'infusion') of Homer 1a protein enhanced spike-induced calcium increase, depending on both the protein concentration and spike frequency. Induction of this enhancement was disrupted by blockers of key molecules of the mGluR-IP3 signalling pathway, including metabotropic glutamate receptors (mGluRs), phospholipase C and IP3Rs. However, infusion of IP3 failed to mimic the effect of Homer 1a, suggesting requirement for a second Homer 1a-mediated signalling as well as the mGluR-IP3 signalling. In contrast to the induction, maintenance of this enhancement was independent of the mGluR-IP3 signalling, taking the form of augmented calcium influx via L-type VDCCs. Presumably due to the VDCC up-regulation, threshold currents for calcium spikes were reduced. Given that Homer 1a induction is thought to down-regulate neural excitability and hence somatic spike firing, this facilitation of calcium spikes concomitant with such attenuated firing may well have a critical impact on bi-directional synaptic plasticity.
支架蛋白家族Homer/Vesl用于将表面受体或通道与内质网钙释放通道偶联。Homer 1a/Vesl-1S被认为以活性依赖的方式调节这种偶联。目前的钙成像和电生理测量表明，Homer 1a上调电压依赖性钙通道（VDCCs），这依赖于肌醇-1,4,5-三磷酸（IP3）受体（IP3Rs）。在大鼠新皮质锥体细胞中，通过膜片吸管扩散进行细胞内注射（称为“灌注”）Homer 1a蛋白，可增强动作电位诱发的钙增加，这取决于蛋白浓度和动作电位频率。mGluR-IP3信号通路关键分子的阻滞剂，包括代谢型谷氨酸受体（mGluRs）、磷脂酶C和IP3Rs，可破坏这种增强作用的诱导。然而，灌注IP3未能模拟Homer 1a的作用，这表明除了mGluR-IP3信号通路外，还需要第二种Homer 1a介导的信号通路。与诱导过程不同，这种增强作用的维持不依赖于mGluR-IP3信号通路，而是通过L型VDCCs增加钙内流的形式实现。推测由于VDCC上调，钙尖峰的阈值电流降低。鉴于Homer 1a的诱导被认为会下调神经兴奋性，从而降低体细胞动作电位发放，这种伴随着发放减弱的钙尖峰促进作用很可能对双向突触可塑性产生关键影响。
