Acid-sensing ion channel 1a is a postsynaptic proton receptor that affects the density of dendritic spines
Acid-sensing ion channel 1a is a postsynaptic proton receptor that affects the density of dendritic spines
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DOI：
10.1073/pnas.0608018103
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发表时间：
2006-10-31
影响因子：
11.1
通讯作者：
Welsh, Michael J.
中科院分区：
文献类型：
--
作者：
Zha, Xiang-ming;Wemmie, John A.;Welsh, Michael J.
脑细胞外质子浓度可能是神经元功能的重要信号。当突触囊泡释放酸性物质进入突触间隙时，质子浓度会发生急性变化，而在缺血和癫痫发作期间，质子浓度会发生慢性变化。然而，检测质子的大脑受体及其生理重要性仍然不确定。使用器官型海马切片和生物射弹转染，我们发现酸敏感离子通道1a（ASIC 1a），位于树突棘，在那里它作为质子受体发挥作用。ASIC 1a也影响棘的密度，大多数兴奋性突触的突触后部位。降低ASIC 1a会减少棘的数量，而过表达ASIC 1a则会产生相反的效果。Ca 2+介导的Ca 2 +/钙调蛋白依赖性蛋白激酶II（CaMKII）信号可能是负责的，因为酸引起了ASIC 1a依赖性升高的脊柱细胞内Ca 2+浓度，降低或增加ASIC 1a水平引起体内CaMKII磷酸化的平行变化。此外，抑制CaMKII阻止ASIC 1a增加棘密度。这些数据表明，ASIC 1a作为突触后质子受体发挥作用，影响细胞内Ca 2+浓度和CaMKII磷酸化，从而影响树突棘的密度。这些结果提供了对质子如何影响大脑功能以及它们如何有助于病理生理学的深入了解。
Extracellular proton concentrations in the brain may be an important-signal for neuron function. Proton concentrations change both acutely when synaptic vesicles release their acidic contents into the synaptic cleft and chronically during ischemia and seizures. However, the brain receptors that detect protons and their physiologic importance remain uncertain. Using organotypic hippocampal slices and biolistic transfection, we found the acid-sensing ion channel 1a (ASIC1a), localized in dendritic spines where it functioned as a proton receptor. ASIC1a also affected the density of spines, the postsynaptic site of most excitatory synapses. Decreasing ASIC1a reduced the number of spines, whereas overexpressing ASIC1a had the opposite effect. Ca2+-mediated Ca2+/calmodulin-dependent protein kinase II (CaMKII) signaling was probably responsible, because acid evoked an ASIC1a-dependent elevation of spine intracellular Ca2+ concentration, and reducing or increasing ASIC1a levels caused parallel changes in CaMKII phosphorylation in vivo. Moreover, inhibiting CaMKII prevented ASIC1a from increasing spine density. These data indicate that ASIC1a functions as a postsynaptic proton receptor that influences intracellular Ca2+ concentration and CaMKII phosphorylation and thereby the density of dendritic spines. The results provide insight into how protons influence brain function and how they may contribute to pathophysiology.