Novel endogenous peptide agonists of cannabinoid receptors
Novel endogenous peptide agonists of cannabinoid receptors
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DOI：
10.1096/fj.09-132142
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发表时间：
2009-09-01
期刊：
影响因子：
4.8
通讯作者：
Devi, Lakshmi A.
中科院分区：
文献类型：
--
作者：
Gomes, Ivone;Grushko, Julia S.;Devi, Lakshmi A.
血加压素(HP)是一种9个残基的α-血红蛋白衍生肽，此前有报道称其功能是CB1大麻受体拮抗剂(1)。在这项研究中，我们报告了来自小鼠脑提取液肽组学分析的质谱仪(MS)数据，鉴定出Hp的N-末端扩展形式含有三个(RVD-Hpα)或两个(Vd-Hpα)额外的氨基酸，以及一个与血加压素(Vd-Hp)序列相似的β-血红蛋白衍生肽(Vd-Hpβ)。结合和功能分析表明，与发挥CB1受体拮抗剂功能的HP相反，RVD-HPα和VD-HPα都具有激动剂的功能。对ERK1/2水平的磷酸化或细胞内钙离子释放的研究表明，这些多肽激活的信号转导途径与内源性大麻素、2-花生四烯基甘油或经典的CB1激动剂HU-210不同。这一发现表明了内源性大麻素受体活性的另一种调节模式。综上所述，这些结果表明，CB1受体参与了来自脂类和多肽衍生信号分子的信号整合。-戈麦斯，I，Grushko，J.S.，Golebiewska，U，Hoogendorn，S.，Gupta，A.，Heimann，A.S.，Ferro，E.S.，Scarlata，S.，Fricker，L.D.，Devi，L.A.新型大麻受体内源性多肽激动剂。FASE B J.23,3020-3029(2009)。Www.fasebj.org
Hemopressin (Hp), a 9-residue alpha-hemoglobin-derived peptide, was previously reported to function as a CB1 cannabinoid receptor antagonist (1). In this study, we report that mass spectrometry (MS) data from peptidomics analyses of mouse brain extracts identified N-terminally extended forms of Hp containing either three (RVD-Hp alpha) or two (VD-Hp alpha) additional amino acids, as well as a beta-hemoglobinderived peptide with sequence similarity to that of hemopressin (VD-Hp beta). Characterization of the alpha-hemoglobin-derived peptides using binding and functional assays shows that in contrast to Hp, which functions as a CB1 cannabinoid receptor antagonist, both RVD-Hp alpha and VD-Hp alpha function as agonists. Studies examining the increase in the phosphorylation of ERK1/2 levels or release of intracellular Ca2+ indicate that these peptides activate a signal transduction pathway distinct from that activated by the endo-cannabinoid, 2-arachidonoylglycerol, or the classic CB1 agonist, Hu-210. This finding suggests an additional mode of regulation of endogenous cannabinoid receptor activity. Taken together, these results suggest that the CB1 receptor is involved in the integration of signals from both lipid-and peptide-derived signaling molecules.-Gomes, I., Grushko, J. S., Golebiewska, U., Hoogendoorn, S., Gupta, A., Heimann, A. S., Ferro, E. S., Scarlata, S., Fricker, L. D., Devi, L. A. Novel endogenous peptide agonists of cannabinoid receptors. FASEB J. 23, 3020-3029 (2009). www.fasebj.org