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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Rapid modulation of spine morphology by the 5-HT_(2A) serotonin receptor through kalirin-7 signaling
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Rapid modulation of spine morphology by the 5-HT_(2A) serotonin receptor through kalirin-7 signaling

机译：5-HT_（2A）5-羟色胺受体通过kalirin-7信号快速调节脊柱形态

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摘要

The 5-HT_(2A) serotonin receptor is the most abundant serotonin receptor subtype in the cortex and is predominantly expressed in pyramidal neurons. The 5-HT_(2A) receptor is a target of several hallucinogens, antipsychotics, anxiolytics, and antidepressants, and it has been associated with several psychiatric disorders, conditions that are also associated with aberrations in dendritic spine morphogenesis. However, the role of 5-HT_(2A) receptors in regulating dendritic spine morphogenesis in cortical neurons is unknown. Here we show that the 5-HT_(2A) receptor is present in a subset of spines, in addition to dendritic shafts. It colocalizes with PSD-95 and with multiple PDZ protein-1 (MUPP1) in a subset of dendritic spines of rat cortical pyramidal neurons. MUPP1 is enriched in postsynaptic density (PSD) fractions, is targeted to spines in pyramidal neurons, and enhances the localization of 5-HT_(2A) receptors to the cell periphery. 5-HT_(2a) receptor activation by the 5-HT_2 receptor agonist DOI induced a transient increase in dendritic spine size, as well as phosphorylation of p21-activated kinase (PAK) in cultured cortical neurons. PAK is a downstream target of the neuronal Rac guanine nucleotide exchange factor (RacGEF) kalirin-7 that is important for spine remodeling. Kalirin-7 regulates dendritic spine morphogenesis in neurons but its role in neuromodu-lator signaling has not been investigated. We show that peptide interference that prevents the localization of kalirin-7 to the postsynaptic density disrupts DOI-induced PAK phosphorylation and spine morphogenesis. These results suggest a potential role for serotonin signaling in modulating spine morphology and kalirin-7's function at cortical synapses.
机译：5-HT_（2A）5-羟色胺受体是皮质中最丰富的5-羟色胺受体亚型，主要在锥体神经元中表达。 5-HT_（2A）受体是几种致幻剂，抗精神病药，抗焦虑药和抗抑郁药的靶标，并且已与多种精神疾病有关，这些疾病也与树突棘形态发生中的畸变有关。但是，尚不清楚5-HT_（2A）受体在调节皮质神经元中树突棘形态发生中的作用。在这里，我们显示5-HT_（2A）受体存在于除了树突轴的一部分棘突中。它在大鼠皮质锥体神经元的树突棘的子集中与PSD-95和多个PDZ蛋白1（MUPP1）共定位。 MUPP1富含突触后密度（PSD）分数，针对锥体神经元中的棘突，并增强5-HT_（2A）受体在细胞周围的定位。 5-HT_2受体激动剂DOI激活5-HT_（2a）受体会导致树突棘大小的瞬时增加，以及在培养的皮层神经元中p21激活激酶（PAK）的磷酸化。 PAK是神经元Rac鸟嘌呤核苷酸交换因子（RacGEF）kalirin-7的下游靶标，对脊柱重塑很重要。 Kalirin-7调节神经元中的树突棘形态发生，但尚未研究其在神经调节信号中的作用。我们表明，防止干扰素对突触后密度的定位的肽干扰干扰DOI诱导PAK磷酸化和脊柱形态发生。这些结果表明5-羟色胺信号传导可能在调节皮质突触中的脊柱形态和kalirin-7功能中发挥潜在作用。

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  • 作者

    Kelly A. Jones; Deepak P. Srivastava; John A. Allen; Ryan T. Strachan; Bryan L. Roth; Peter Penzes;

  • 作者单位

    Department of Physiology, Northwestern University Feinberg School of Medicine, Chicago, IL 60611;

    Department of Physiology, Northwestern University Feinberg School of Medicine, Chicago, IL 60611;

    Department of Pharmacology, University of North Carolina, Chapel Hill, NC 27599;

    Department of Biochemistry, Case Western Reserve University Medical School, Cleveland, OH 44106;

    Department of Pharmacology, University of North Carolina, Chapel Hill, NC 27599;

    Department of Physiology, Northwestern University Feinberg School of Medicine, Chicago, IL 60611;

  • 收录信息 美国《科学引文索引》(SCI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类
  • 关键词

    GPCR; neuromodulator; PAK; Rac; synapse;

    机译：GPCR;神经调节剂PAK;Rac;突触;

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