Gabapentin receptor alpha2delta-1 is a neuronal thrombospondin receptor responsible for excitatory CNS synaptogenesis.
Gabapentin receptor alpha2delta-1 is a neuronal thrombospondin receptor responsible for excitatory CNS synaptogenesis.
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DOI：
10.1016/j.cell.2009.09.025
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发表时间：
2009-10-16
期刊：
影响因子：
64.5
通讯作者：
Barres BA
中科院分区：
文献类型：
--
作者：
Eroglu C;Allen NJ;Susman MW;O'Rourke NA;Park CY;Ozkan E;Chakraborty C;Mulinyawe SB;Annis DS;Huberman AD;Green EM;Lawler J;Dolmetsch R;Garcia KC;Smith SJ;Luo ZD;Rosenthal A;Mosher DF;Barres BA
突触是不对称的细胞粘附，对神经系统的发育和功能至关重要，但诱导其形成的机制还不清楚。我们以前已经确定血小板反应蛋白作为星形胶质细胞分泌的蛋白质，促进中枢神经系统突触。在这里，我们确定了参与CNS突触形成的神经元血小板反应蛋白受体α2δ-1，抗癫痫和镇痛药物加巴喷丁的受体。我们发现α2δ-1的VWF-A结构域与所有血小板反应蛋白共有的表皮生长因子样重复序列相互作用。α2δ-1过表达增加体外和体内突触发生，并且是体外血小板反应蛋白和星形胶质细胞诱导的突触形成所需的突触后。加巴喷丁拮抗血小板反应蛋白与α2δ-1的结合，并在体外和体内有效抑制兴奋性突触形成。这些发现确定α2δ-1是参与兴奋性突触形成的受体，并表明加巴喷丁可能通过阻断新突触形成而发挥治疗作用。
Synapses are asymmetric cellular adhesions that are critical for nervous system development and function, but the mechanisms that induce their formation are not well understood. We have previously identified thrombospondin as an astrocyte-secreted protein that promotes CNS synaptogenesis. Here we identify the neuronal thrombospondin receptor involved in CNS synapse formation as α2δ–1, the receptor for the anti-epileptic and analgesic drug gabapentin. We show that the VWF-A domain of α2δ–1 interacts with the epidermal growth factor-like repeats common to all thrombospondins. α2δ–1 overexpression increases synaptogenesis in vitro and in vivo and is required postsynaptically for thrombospondin and astrocyte-induced synapse formation in vitro. Gabapentin antagonizes thrombospondin binding to α2δ–1 and powerfully inhibits excitatory synapse formation in vitro and in vivo. These findings identify α2δ–1 as a receptor involved in excitatory synapse formation and suggest that gabapentin may function therapeutically by blocking new synapse formation.
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影响因子：
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