Tallent Melanie K, Varghis Neal, Skorobogatko Yuliya, Hernandez-Cuebas Lisa, Whelan Kelly, Vocadlo David J, Vosseller Keith
Department of Biochemistry and Molecular Biology and Department of Pharmacology and Physiology, Drexel University College of Medicine, Philadelphia, Pennsylvania 19102 and the Department of Chemistry, Simon Fraser University, Burnaby, British Columbia V5A 1S6, Canada.
Department of Biochemistry and Molecular Biology and Department of Pharmacology and Physiology, Drexel University College of Medicine, Philadelphia, Pennsylvania 19102 and the Department of Chemistry, Simon Fraser University, Burnaby, British Columbia V5A 1S6, Canada.
J Biol Chem. 2009 Jan 2;284(1):174-181. doi: 10.1074/jbc.M807431200. Epub 2008 Nov 11.
O-Linked N-acetylglucosamine (O-GlcNAc) is a cytosolic and nuclear carbohydrate post-translational modification most abundant in brain. We recently reported uniquely extensive O-GlcNAc modification of proteins that function in synaptic vesicle release and post-synaptic signal transduction. Here we examined potential roles for O-GlcNAc in mouse hippocampal synaptic transmission and plasticity. O-GlcNAc modifications and the enzyme catalyzing their addition (O-GlcNAc transferase) were enriched in hippocampal synaptosomes. Pharmacological elevation or reduction of O-GlcNAc levels had no effect on Schaffer collateral CA1 basal hippocampal synaptic transmission. However, in vivo elevation of O-GlcNAc levels enhanced long term potentiation (LTP), an electrophysiological correlate to some forms of learning/memory. Reciprocally, pharmacological reduction of O-GlcNAc levels blocked LTP. Additionally, elevated O-GlcNAc led to reduced paired-pulse facilitation, a form of short term plasticity attributed to presynaptic mechanisms. Synapsin I and II are presynaptic proteins that increase synaptic vesicle availability for release when phosphorylated, thus contributing to hippocampal synaptic plasticity. Synapsins are among the most extensively O-GlcNAc-modified proteins known. Elevating O-GlcNAc levels increased phosphorylation of Synapsin I/II at serine 9 (cAMP-dependent protein kinase substrate site), serine 62/67 (Erk 1/2 (MAPK 1/2) substrate site), and serine 603 (calmodulin kinase II site). Activation-specific phosphorylation events on Erk 1/2 and calmodulin kinase II, two proteins required for CA1 hippocampal LTP establishment, were increased in response to elevation of O-GlcNAc levels. Thus, O-GlcNAc is a novel regulatory signaling component of excitatory synapses, with specific roles in synaptic plasticity that involve interplay with phosphorylation.
O-连接的N-乙酰葡糖胺（O-GlcNAc）是一种存在于胞质和细胞核中的碳水化合物翻译后修饰，在大脑中含量最为丰富。我们最近报道了在突触小泡释放和突触后信号转导中起作用的蛋白质存在独特的广泛O-GlcNAc修饰。在此，我们研究了O-GlcNAc在小鼠海马突触传递和可塑性中的潜在作用。O-GlcNAc修饰以及催化其添加的酶（O-GlcNAc转移酶）在海马突触体中富集。药理学上提高或降低O-GlcNAc水平对海马体Schaffer侧支- CA1基础突触传递没有影响。然而，体内提高O-GlcNAc水平增强了长时程增强（LTP），这是一种与某些形式的学习/记忆相关的电生理现象。相反，药理学上降低O-GlcNAc水平则阻断了LTP。此外，O-GlcNAc升高导致双脉冲易化降低，双脉冲易化是一种归因于突触前机制的短期可塑性形式。突触素I和II是突触前蛋白，磷酸化时会增加可供释放的突触小泡数量，从而有助于海马突触可塑性。突触素是已知O-GlcNAc修饰最广泛的蛋白质之一。提高O-GlcNAc水平会增加突触素I/II在丝氨酸9（环磷酸腺苷依赖性蛋白激酶底物位点）、丝氨酸62/67（细胞外信号调节激酶1/2（丝裂原活化蛋白激酶1/2）底物位点）和丝氨酸603（钙调蛋白激酶II位点）的磷酸化。对于海马体CA1区LTP建立所必需的两种蛋白质，细胞外信号调节激酶1/2和钙调蛋白激酶II的激活特异性磷酸化事件，会随着O-GlcNAc水平的升高而增加。因此，O-GlcNAc是兴奋性突触的一种新型调节信号成分，在涉及与磷酸化相互作用的突触可塑性中具有特定作用。
