• 文献检索
  • 文档翻译
  • 深度研究
  • 学术资讯
  • Suppr Zotero 插件Zotero 插件
  • 邀请有礼
  • 套餐&价格
  • 历史记录
应用&插件
Suppr Zotero 插件Zotero 插件浏览器插件Mac 客户端Windows 客户端微信小程序
定价
高级版会员购买积分包购买API积分包
服务
文献检索文档翻译深度研究API 文档MCP 服务
关于我们
关于 Suppr公司介绍联系我们用户协议隐私条款
关注我们

Suppr 超能文献

核心技术专利：CN118964589B侵权必究
粤ICP备2023148730 号-1Suppr @ 2026

文献检索

告别复杂PubMed语法，用中文像聊天一样搜索，搜遍4000万医学文献。AI智能推荐，让科研检索更轻松。

立即免费搜索

文件翻译

保留排版，准确专业，支持PDF/Word/PPT等文件格式，支持 12+语言互译。

免费翻译文档

深度研究

AI帮你快速写综述，25分钟生成高质量综述，智能提取关键信息，辅助科研写作。

立即免费体验

Ghrelin 与 GHS-R1a、GHS-R1b 和多巴胺 D 受体的复合物定位于腹侧被盖区，作为 Ghrelin 多巴胺能作用的主要介质。

Complexes of Ghrelin GHS-R1a, GHS-R1b, and Dopamine D Receptors Localized in the Ventral Tegmental Area as Main Mediators of the Dopaminergic Effects of Ghrelin.

机构信息

Department of Biochemistry and Molecular Biology, Faculty of Pharmacy and Food Sciences, University of Barcelona, Barcelona, 08028, Spain.

Integrative Neurobiology Section, Molecular Targets and Medications Discovery Branch, National Institute on Drug Abuse, Intramural Research Program, National Institutes of Health, Baltimore, Maryland 21224.

出版信息

J Neurosci. 2022 Feb 9;42(6):940-953. doi: 10.1523/JNEUROSCI.1151-21.2021. Epub 2021 Dec 7.

DOI:10.1523/JNEUROSCI.1151-21.2021
PMID:34876469
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC8824505/
Abstract

Ghrelin receptor, also known as growth hormone secretagogue receptor (GHS-R1a), is coexpressed with its truncated isoform GHS-R1b, which does not bind ghrelin or signal, but oligomerizes with GHS-R1a, exerting a complex modulatory role that depends on its relative expression. D dopamine receptor (D1R) and D5R constitute the two D-like receptor subtypes. Previous studies showed that GHS-R1b also facilitates oligomerization of GHS-R1a with D1R, conferring GHS-R1a distinctive pharmacological properties. Those include a switch in the preferred coupling of GHS-R1a from Gq to Gs and the ability of D1R/D5R agonists and antagonists to counteract GHS-R1a signaling. Activation of ghrelin receptors localized in the ventral tegmental area (VTA) seems to play a significant role in the contribution of ghrelin to motivated behavior. In view of the evidence indicating that dopaminergic cells of the VTA express ghrelin receptors and D5R, but not D1R, we investigated the possible existence of functional GHS-R1a:GHS-R1b:D5R oligomeric complexes in the VTA. GHS-R1a:GHS-R1b:D5R oligomers were first demonstrated in mammalian transfected cells, and their pharmacological properties were found to be different from those of GHS-R1a:GHS-R1b:D1R oligomers, including weak Gs coupling and the ability of D1R/D5R antagonists, but not agonists, to counteract the effects of ghrelin. However, analyzing the effect of ghrelin in the rodent VTA on MAPK activation with experiments, on somatodendritic dopamine release with microdialysis and on the activation of dopaminergic cells with patch-clamp electrophysiology, provided evidence for a predominant role of GHS-R1a:GHS-R1b:D1R oligomers in the rodent VTA as main mediators of the dopaminergic effects of ghrelin. The activation of ghrelin receptors localized in the ventral tegmental area (VTA) plays a significant role in the contribution of ghrelin to motivated behavior. We present evidence that indicates these receptors form part of oligomeric complexes that include the functional ghrelin receptor GHS-R1a, its truncated nonsignaling isoform GHS-R1b, and the dopamine D receptor (D1R). The binding of ghrelin to these complexes promotes activation of the dopaminergic neurons of the VTA by activation of adenylyl cyclase-protein kinase A signaling, which can be counteracted by both GHS-R1a and D1R antagonists. Our study provides evidence for a predominant role of GHS-R1a:GHS-R1b:D1R oligomers in rodent VTA as main mediators of the dopaminergic effects of ghrelin.

摘要

生长激素促分泌素受体（GHS-R1a）又被称为胃饥饿素受体，它与截短的同工型 GHS-R1b 共同表达，后者不与胃饥饿素结合或发出信号，但与 GHS-R1a 寡聚化，发挥复杂的调节作用，这种作用依赖于其相对表达。D 型多巴胺受体（D1R）和 D5R 构成两种 D 样受体亚型。先前的研究表明，GHS-R1b 还促进 GHS-R1a 与 D1R 的寡聚化，赋予 GHS-R1a 独特的药理学特性。这些特性包括 GHS-R1a 从 Gq 向 Gs 的偶联偏好发生转变，以及 D1R/D5R 激动剂和拮抗剂拮抗 GHS-R1a 信号的能力。定位于腹侧被盖区（VTA）的胃饥饿素受体的激活似乎在胃饥饿素对动机行为的贡献中发挥重要作用。鉴于证据表明 VTA 的多巴胺能细胞表达胃饥饿素受体和 D5R，但不表达 D1R，我们研究了 VTA 中是否存在功能性 GHS-R1a：GHS-R1b：D5R 寡聚体复合物。首先在哺乳动物转染细胞中证明了 GHS-R1a：GHS-R1b：D5R 寡聚体的存在，并且发现它们的药理学特性与 GHS-R1a：GHS-R1b：D1R 寡聚体不同，包括弱 Gs 偶联以及 D1R/D5R 拮抗剂而非激动剂拮抗胃饥饿素作用的能力。然而，通过 实验分析胃饥饿素在啮齿动物 VTA 中对 MAPK 激活的作用，通过 微透析分析对 somatodendritic 多巴胺释放的作用，以及通过膜片钳电生理学分析对多巴胺能细胞激活的作用，为 GHS-R1a：GHS-R1b：D1R 寡聚体在啮齿动物 VTA 中作为胃饥饿素的多巴胺效应的主要介质发挥主要作用提供了证据。定位于腹侧被盖区（VTA）的胃饥饿素受体的激活在胃饥饿素对动机行为的贡献中起着重要作用。我们提供的证据表明，这些受体构成包含功能性胃饥饿素受体 GHS-R1a、其截短的无信号同工型 GHS-R1b 和多巴胺 D 受体（D1R）的寡聚体复合物的一部分。胃饥饿素与这些复合物的结合通过激活腺苷酸环化酶-蛋白激酶 A 信号转导促进 VTA 中的多巴胺能神经元的激活，这可以被 GHS-R1a 和 D1R 拮抗剂共同拮抗。我们的研究为 GHS-R1a：GHS-R1b：D1R 寡聚体在啮齿动物 VTA 中作为胃饥饿素的多巴胺效应的主要介质发挥主要作用提供了证据。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/92b9/8824505/b01b3a4deee8/SN-JNSJ210885F008.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/92b9/8824505/30b5b712bc5b/SN-JNSJ210885F001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/92b9/8824505/658965fc4aab/SN-JNSJ210885F002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/92b9/8824505/119faf566e48/SN-JNSJ210885F003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/92b9/8824505/30d41b3d8767/SN-JNSJ210885F004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/92b9/8824505/86a97b1deae8/SN-JNSJ210885F005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/92b9/8824505/eb811b91c844/SN-JNSJ210885F006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/92b9/8824505/b1b85a181375/SN-JNSJ210885F007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/92b9/8824505/b01b3a4deee8/SN-JNSJ210885F008.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/92b9/8824505/30b5b712bc5b/SN-JNSJ210885F001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/92b9/8824505/658965fc4aab/SN-JNSJ210885F002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/92b9/8824505/119faf566e48/SN-JNSJ210885F003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/92b9/8824505/30d41b3d8767/SN-JNSJ210885F004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/92b9/8824505/86a97b1deae8/SN-JNSJ210885F005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/92b9/8824505/eb811b91c844/SN-JNSJ210885F006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/92b9/8824505/b1b85a181375/SN-JNSJ210885F007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/92b9/8824505/b01b3a4deee8/SN-JNSJ210885F008.jpg

相似文献

1
Complexes of Ghrelin GHS-R1a, GHS-R1b, and Dopamine D Receptors Localized in the Ventral Tegmental Area as Main Mediators of the Dopaminergic Effects of Ghrelin.Ghrelin 与 GHS-R1a、GHS-R1b 和多巴胺 D 受体的复合物定位于腹侧被盖区，作为 Ghrelin 多巴胺能作用的主要介质。
J Neurosci. 2022 Feb 9;42(6):940-953. doi: 10.1523/JNEUROSCI.1151-21.2021. Epub 2021 Dec 7.
2
A Significant Role of the Truncated Ghrelin Receptor GHS-R1b in Ghrelin-induced Signaling in Neurons.截短型胃饥饿素受体GHS-R1b在胃饥饿素诱导的神经元信号传导中的重要作用。
J Biol Chem. 2016 Jun 17;291(25):13048-62. doi: 10.1074/jbc.M116.715144. Epub 2016 Apr 25.
3
Ghrelin receptor (GHS-R1A) agonists show potential as interventive agents during aging.胃饥饿素受体（GHS-R1A）激动剂在衰老过程中显示出作为干预剂的潜力。
Ann N Y Acad Sci. 2007 Nov;1119:147-64. doi: 10.1196/annals.1404.023.
4
Quinpirole ameliorates nigral dopaminergic neuron damage in Parkinson's disease mouse model through activating GHS-R1a/DR heterodimers.喹吡罗改善帕金森病小鼠模型中黑质多巴胺能神经元损伤是通过激活 GHS-R1a/DR 异源二聚体实现的。
Acta Pharmacol Sin. 2023 Aug;44(8):1564-1575. doi: 10.1038/s41401-023-01063-0. Epub 2023 Mar 10.
5
Ghrelin and GHS-R1A signaling within the ventral and laterodorsal tegmental area regulate sexual behavior in sexually naïve male mice.腹侧和背外侧被盖区内的胃饥饿素和生长激素释放激素受体1A信号通路调节性幼稚雄性小鼠的性行为。
Psychoneuroendocrinology. 2015 Dec;62:392-402. doi: 10.1016/j.psyneuen.2015.09.009. Epub 2015 Sep 10.
6
Concomitant release of ventral tegmental acetylcholine and accumbal dopamine by ghrelin in rats.生长激素释放肽在大鼠中引起腹侧被盖区乙酰胆碱和伏隔核多巴胺的共同释放。
PLoS One. 2012;7(11):e49557. doi: 10.1371/journal.pone.0049557. Epub 2012 Nov 14.
7
A ghrelin receptor antagonist reduces the ability of ghrelin, alcohol or amphetamine to induce a dopamine release in the ventral tegmental area and in nucleus accumbens shell in rats.一种胃饥饿素受体拮抗剂可降低胃饥饿素、酒精或安非他命在大鼠腹侧被盖区和伏隔核壳中诱导多巴胺释放的能力。
Eur J Pharmacol. 2021 May 15;899:174039. doi: 10.1016/j.ejphar.2021.174039. Epub 2021 Mar 15.
8
Ghrelin receptor activation in the ventral tegmental area amplified instrumental responding but not the excitatory influence of Pavlovian stimuli on instrumental responding.腹侧被盖区中的胃饥饿素受体激活增强了工具性反应，但未增强经典条件刺激对工具性反应的兴奋性影响。
Neurobiol Learn Mem. 2016 Oct;134 Pt B:210-5. doi: 10.1016/j.nlm.2016.08.003. Epub 2016 Aug 9.
9
The truncated ghrelin receptor polypeptide (GHS-R1b) is localized in the endoplasmic reticulum where it forms heterodimers with ghrelin receptors (GHS-R1a) to attenuate their cell surface expression.截短的胃饥饿素受体多肽 (GHS-R1b) 定位于内质网，在那里它与胃饥饿素受体 (GHS-R1a) 形成异二聚体，从而减弱其细胞表面表达。
Mol Cell Endocrinol. 2012 Jan 2;348(1):247-54. doi: 10.1016/j.mce.2011.08.034. Epub 2011 Aug 31.
10
Ghrelin receptor antagonism and satiety attenuate Pavlovian-instrumental transfer.ghrelin 受体拮抗和饱腹感会减弱巴甫洛夫式条件反射-工具性条件反射的传递。
Neurobiol Learn Mem. 2024 Jan;207:107864. doi: 10.1016/j.nlm.2023.107864. Epub 2023 Nov 23.

引用本文的文献

1
Midbrain ghrelin receptor signalling regulates binge drinking in a sex specific manner.中脑胃饥饿素受体信号传导以性别特异性方式调节暴饮。
Nat Commun. 2025 Mar 15;16(1):2568. doi: 10.1038/s41467-025-57880-w.
2
Antimicrobial Neuropeptides and Their Receptors: Immunoregulator and Therapeutic Targets for Immune Disorders.抗菌神经肽及其受体：免疫失调的免疫调节剂和治疗靶点
Molecules. 2025 Jan 27;30(3):568. doi: 10.3390/molecules30030568.
3
LEAP2, a ghrelin receptor inverse agonist, and its effect on alcohol-related responses in rodents.

本文引用的文献

1
A ghrelin receptor antagonist reduces the ability of ghrelin, alcohol or amphetamine to induce a dopamine release in the ventral tegmental area and in nucleus accumbens shell in rats.一种胃饥饿素受体拮抗剂可降低胃饥饿素、酒精或安非他命在大鼠腹侧被盖区和伏隔核壳中诱导多巴胺释放的能力。
Eur J Pharmacol. 2021 May 15;899:174039. doi: 10.1016/j.ejphar.2021.174039. Epub 2021 Mar 15.
2
Discovery of a macromolecular complex mediating the hunger suppressive actions of cocaine: Structural and functional properties.发现介导可卡因抑制饥饿作用的大分子复合物：结构和功能特性。
Addict Biol. 2021 Sep;26(5):e13017. doi: 10.1111/adb.13017. Epub 2021 Feb 8.
3
LEAP2，一种胃饥饿素受体反向激动剂，及其对啮齿动物酒精相关反应的影响。
Transl Psychiatry. 2024 Oct 2;14(1):401. doi: 10.1038/s41398-024-03136-y.
4
Visualization of the existence of growth hormone secretagogue receptor in the rat nucleus accumbens.可视化生长激素促分泌素受体在大鼠伏隔核中的存在。
Mol Brain. 2024 Jun 13;17(1):37. doi: 10.1186/s13041-024-01109-2.
5
Ghrelin in Focus: Dissecting Its Critical Roles in Gastrointestinal Pathologies and Therapies.聚焦胃饥饿素：剖析其在胃肠道疾病及治疗中的关键作用
Curr Issues Mol Biol. 2024 Jan 22;46(1):948-964. doi: 10.3390/cimb46010061.
6
Ghrelin receptor antagonist JMV2959 blunts cocaine and oxycodone drug-seeking, but not self-administration, in male rats.胃饥饿素受体拮抗剂JMV2959可减弱雄性大鼠对可卡因和羟考酮的觅药行为，但不影响其自我给药行为。
Front Pharmacol. 2023 Sep 19;14:1268366. doi: 10.3389/fphar.2023.1268366. eCollection 2023.
7
Neuropeptides Modulate Feeding via the Dopamine Reward Pathway.神经肽通过多巴胺奖励途径调节摄食。
Neurochem Res. 2023 Sep;48(9):2622-2643. doi: 10.1007/s11064-023-03954-4. Epub 2023 May 26.
8
Metabolic hormone action in the VTA: Reward-directed behavior and mechanistic insights.腹侧被盖区代谢激素的作用：奖励导向行为和机制见解。
Physiol Behav. 2023 Sep 1;268:114236. doi: 10.1016/j.physbeh.2023.114236. Epub 2023 May 12.
9
Toward a consensus nomenclature for ghrelin, its non-acylated form, liver expressed antimicrobial peptide 2 and growth hormone secretagogue receptor.朝向生长激素促分泌素受体、其未酰化形式、肝表达抗菌肽 2 和促胃液素共识命名法。
J Neuroendocrinol. 2023 Jan;35(1):e13224. doi: 10.1111/jne.13224. Epub 2022 Dec 29.
10
Glucocorticoids, stress and eating: The mediating role of appetite-regulating hormones.糖皮质激素、应激与进食：食欲调节激素的中介作用。
Obes Rev. 2023 Mar;24(3):e13539. doi: 10.1111/obr.13539. Epub 2022 Dec 8.
Chronic unpredictable stress promotes cell-specific plasticity in prefrontal cortex D1 and D2 pyramidal neurons.
慢性不可预测应激促进前额叶皮层D1和D2锥体神经元的细胞特异性可塑性。
Neurobiol Stress. 2019 Mar 8;10:100152. doi: 10.1016/j.ynstr.2019.100152. eCollection 2019 Feb.
4
Opioid-galanin receptor heteromers mediate the dopaminergic effects of opioids.阿片类物质-甘丙肽受体同聚体介导阿片类物质的多巴胺能效应。
J Clin Invest. 2019 Mar 26;129(7):2730-2744. doi: 10.1172/JCI126912.
5
Ghrelin Receptor Influence on Cocaine Reward is Not Directly Dependent on Peripheral Acyl-Ghrelin.生长激素释放肽受体对可卡因奖赏的影响并不直接依赖于外周酰化生长激素释放肽。
Sci Rep. 2019 Feb 12;9(1):1841. doi: 10.1038/s41598-019-38549-z.
6
Ghrelin: From a gut hormone to a potential therapeutic target for alcohol use disorder.Ghrelin：从肠道激素到酒精使用障碍的潜在治疗靶点。
Physiol Behav. 2019 May 15;204:49-57. doi: 10.1016/j.physbeh.2019.02.008. Epub 2019 Feb 7.
7
Ghrelin and food reward.胃饥饿素与食物奖赏。
Neuropharmacology. 2019 Apr;148:131-138. doi: 10.1016/j.neuropharm.2019.01.001. Epub 2019 Jan 5.
8
Brain accessibility delineates the central effects of circulating ghrelin.脑可及性描绘了循环 ghrelin 的中枢作用。
J Neuroendocrinol. 2019 Jul;31(7):e12677. doi: 10.1111/jne.12677. Epub 2019 Feb 12.
9
N-Terminal Liver-Expressed Antimicrobial Peptide 2 (LEAP2) Region Exhibits Inverse Agonist Activity toward the Ghrelin Receptor.N-末端肝表达抗菌肽 2（LEAP2）区域对胃饥饿素受体表现出反向激动剂活性。
J Med Chem. 2019 Jan 24;62(2):965-973. doi: 10.1021/acs.jmedchem.8b01644. Epub 2018 Dec 24.
10
Differential functional selectivity and downstream signaling bias of ghrelin receptor antagonists and inverse agonists.胃饥饿素受体拮抗剂和反向激动剂的功能选择性和下游信号转导偏倚的差异。
FASEB J. 2019 Jan;33(1):518-531. doi: 10.1096/fj.201800655R. Epub 2018 Jul 18.