更新于：2024-11-01

mGluR1

更新于：2024-11-01

基本信息

别名

glutamate metabotropic receptor 1、glutamate receptor, metabotropic 1、GPRC1A

+ [6]

简介

G-protein coupled receptor for glutamate. Ligand binding causes a conformation change that triggers signaling via guanine nucleotide-binding proteins (G proteins) and modulates the activity of down-stream effectors. Signaling activates a phosphatidylinositol-calcium second messenger system. May participate in the central action of glutamate in the CNS, such as long-term potentiation in the hippocampus and long-term depression in the cerebellum (PubMed:24603153, PubMed:28886343, PubMed:7476890). May function in the light response in the retina (By similarity).

关联

项与 mGluR1 相关的药物

14-M-0016

靶点

mGluR1

作用机制

mGluR1拮抗剂

在研机构

National Institutes of Health

原研机构

National Institutes of Health

在研适应症

诊断试剂

非在研适应症-

最高研发阶段临床1期

首次获批国家/地区-

首次获批日期1800-01-20

BAY-367620

靶点

mGluR1

作用机制

mGluR1拮抗剂

在研机构

原研机构

在研适应症

非在研适应症

最高研发阶段临床前

首次获批国家/地区-

首次获批日期1800-01-20

FTIDC

靶点

mGluR1

作用机制

mGluR1拮抗剂

在研机构

Banyu Pharmaceutical Co. Ltd.

原研机构

Banyu Pharmaceutical Co. Ltd.

在研适应症-

非在研适应症-

最高研发阶段临床前

首次获批国家/地区-

首次获批日期1800-01-20

项与 mGluR1 相关的临床试验

NCT02230592 / CompletedN/AIIT

PET Imaging of Brain mGluR1 Receptors Using [18F]FIMX

Objective:
Metabotropic glutamate receptors (mGluRs) are G-protein coupled receptors that respond to glutamate by activating proteins inside nerve cells that affect cell metabolism, thereby fine-tuning the signals sent between cells to maintain balance in neuronal activity. mGluR subtype 1 (mGluR1s) are located in several brain regions, including the cerebellum, hippocampus, olfactory bulb, and basal ganglia. mGluR1 activation stimulates phospholipase C, resulting in phosphoinositide hydrolysis and increased intracellular calcium levels. Successful development of a positron emission tomography (PET) ligand to image mGlurR1 would impact clinical management of brain disorders characterized by disruptions in glutamatergic transmission, including anxiety and stress disorders, drug addiction, epilepsy, Huntington s disease, and Parkinson s disease. However, detailed study of mGluR1s has heretofore been hindered by the lack of high affinity and selective ligands for this receptor subtype.
The present protocol will evaluate the ability of a new PET ligand, [18F]FIMX, to image and quantify mGluR1 in the brain of healthy human volunteers. This protocol covers four phases:
Phase 0: screening whole-body scan;
Phase 1: kinetic brain imaging to quantify mGluR1 in brain relative to concurrent measurement of the parent radioligand in arterial plasma;
Phase 2: if the tracer is successful in Phase 1, we will estimate radiation-absorbed doses of [18F]FIMX by performing whole body imaging;
Phase 3: test-retest analysis of brain binding relative to concurrent measurement of the parent radioligand in arterial plasma.
Study Population:
Healthy adult female and male volunteers (n=22, ages 18 to 55) will undergo brain or whole-body imaging..
Design:
This study will begin with a screening whole-body scan to confirm that the radioactivity has fairly broad distribution in several organs. For absolute quantification of mGluR1, 22 healthy controls will have brain PET imaging using [18F]FIMX and an arterial line. Up to 12 of them will have a test-retest scan. Eight additional subjects will have a whole body PET scan for dosimetry, which does not require an arterial line.

Outcome Measures
To assess absolute quantitation of mGluR1 with [18F]FIMX, we will primarily use two outcome measures: the identifiability and time stability of distribution volume calculated with compartmental modeling. In test-retest study, we will calculate the retest variability. To assess whole-body biodistribution and dosimetry of [18F]FIMX we will use the organ time-activity curves....

开始日期2013-11-08

申办/合作机构

National Institute of Mental Health

NCT01420952 / Terminated临床1期IIT

PET Imaging of Brain mGlu1 Receptors Using [11]LY2428703

Background:
- (11C)mGlu1 is a new drug that helps to show where a protein, mGluR1, is found in the brain. The drug contains a small amount of radioactivity that can be detected by imaging studies like positron emission tomography (PET) scans. By looking at the mGluR1 receptors, researchers hope to better understand how they are involved in general health, brain disorders, and addiction.
Objectives:
To test how (11C)mGlu1 is distributed in the brain and body.
To measure how mGluR1 receptors display (11C)mGlu1 during imaging studies.
Eligibility:
- Healthy volunteers between 18 and 50 years of age.
Design:
Participants will be screened with a medical history, physical exam, and blood and urine tests. This study requires four visits to the NIH Clinical Center.
Participants will have an initial evaluation, a magnetic resonance imaging (MRI) scan, a PET scan, and a final blood sample after the PET scan, all at different visits.
The MRI and PET scans will focus on the brain. Participants will receive (11C)mGlu1, and have scans to see how it shows up in the brain.
Some participants will have whole body imaging studies to see how (11C)mGlu1 shows up in the body.

开始日期2011-07-29

申办/合作机构

National Institute of Mental Health

100 项与 mGluR1 相关的临床结果

登录后查看更多信息

100 项与 mGluR1 相关的转化医学

登录后查看更多信息

0 项与 mGluR1 相关的专利（医药）

登录后查看更多信息

1,908

项与 mGluR1 相关的文献（医药）

2024-12-01·Pharmacology Biochemistry and Behavior

Replication and extension of the subregion selectivity of glutamate-related changes within the nucleus accumbens associated with the incubation of cocaine-craving

Article

作者: Travis, Katherine O ; Miller, Bailey W ; Kippin, Tod E ; Webb, Sierra M. ; Miller, Bailey W. ; Wroten, Melissa G ; Kippin, Tod E. ; Szumlinski, Karen K. ; Wroten, Melissa G. ; Sacramento, Arianne ; Szumlinski, Karen K ; Webb, Sierra M ; Ben-Shahar, Osnat ; Travis, Katherine O.

Cue-elicited drug-seeking behavior intensifies with the passage of time during withdrawal from drug taking and this "incubation of cocaine-craving" involves alterations in nucleus accumbens (NA) glutamate transmission. Here, we employed a combination of in vivo microdialysis and immunoblotting approaches to further examine changes in biochemical indices of glutamate transmission within NA subregions that accompany the incubation of cocaine-craving exhibited by male rats with a 10-day history of 6-h access to intravenous cocaine (0.25 mg/infusion). Immunoblotting on whole cell lysates from the core subregion (NAc core) revealed interactions between cocaine self-administration history, withdrawal and drug cue re-exposure for Homer2a/b, mGlu1, and GluN2b expression, as well as indices of Akt and ERK activity. With the exception of PKCε phosphorylation, most protein changes within the shell subregion (NAc shell) depended on drug cue re-exposure and cocaine history rather than varying in a consistent time-dependent manner. Reduced basal extracellular glutamate content was apparent only in the NAc core of cocaine-experienced rats during protracted (30 days) withdrawal and this was accompanied by a markedly blunted capacity of the mGlu1/5 agonist DHPG to elevate glutamate levels within this subregion. Finally, over-expressing neither Homer1c nor Homer2b within the NAc core during protracted cocaine withdrawal altered the magnitude of cue-elicited responding, its extinction or cocaine-primed reinstatement of drug-seeking behavior. The present findings are consistent with the extant literature implicating changes in Group 1 mGlu receptor function within the NAc core subregion as central to incubated cocaine-craving and provide further evidence against a major role for Homer proteins in gating incubated cocaine-craving. Further, our results provide novel correlational evidence implicating elevated Akt and blunted ERK activity within the NAc core as potential contributors to the expression of incubated cocaine-craving, worthy of future investigation.

2024-12-01·International Journal of Surgical Pathology

GRM1-Rearranged Chondromyxoid Fibroma With FGF23 Expression: A Potential Pitfall in Small Biopsies

Article

作者: Hameed, Meera ; Zhang, Yanming ; Machado, Isidro ; Bilsky, Mark H. ; Linos, Konstantinos ; Sharma, Aarti E. ; Hwang, Sinchun

The clinical, radiological, and histopathological features of chondromyxoid fibroma can sometimes resemble those of other benign or malignant tumors. Recently, recurrent GRM1 rearrangements have been identified in chondromyxoid fibroma, and GRM1 positivity by immunohistochemistry has emerged as a dependable surrogate marker for this molecular alteration. Phosphaturic mesenchymal tumor is a rare tumor that often exhibits overexpression of fibroblastic growth factor 23 (FGF23) through various mechanisms. In this report, we present a case of GRM1-rearranged chondromyxoid fibroma that also exhibited FGF23 expression via in situ hybridization, posing significant diagnostic challenges during workup of the initial core biopsy. We hope that this case can serve as an educational resource, shedding light on a rare diagnostic pitfall.

2024-11-01·British Journal of Pharmacology

SCA44‐ and SCAR13‐associated GRM1 mutations affect metabotropic glutamate receptor 1 function through distinct mechanisms

Article

作者: Gregory, Karen J. ; Hellyer, Shane D. ; Langiu, Monica ; Muraleetharan, Ashwin ; Wang, Yuyang

Background and PurposeMetabotropic glutamate receptor 1 (mGlu1) is a promising therapeutic target for neurodegenerative CNS disorders including spinocerebellar ataxias (SCAs). Clinical reports have identified naturally‐occurring mGlu1 mutations in rare SCA subtypes and linked symptoms to mGlu1 mutations. However, how mutations alter mGlu1 function remains unknown, as does amenability of receptor function to pharmacological rescue. Here, we explored SCA‐associated mutation effects on mGlu1 cell surface expression, canonical signal transduction and allosteric ligand pharmacology.Experimental ApproachOrthosteric agonists, positive allosteric modulators (PAMs) and negative allosteric modulators (NAMs) were assessed at two functional endpoints (iCa2+ mobilisation and inositol 1‐phosphate [IP1] accumulation) in FlpIn Trex HEK293A cell lines expressing five mutant mGlu1 subtypes. Key pharmacological parameters including ligand potency, affinity and cooperativity were derived using operational models of agonism and allostery.Key ResultsmGlu1 mutants exhibited differential impacts on mGlu1 expression, with a C‐terminus truncation significantly reducing surface expression. Mutations differentially influenced orthosteric ligand affinity, efficacy and functional cooperativity between allosteric and orthosteric ligands. Loss‐of‐function mutations L454F and N885del reduced orthosteric affinity and efficacy, respectively. A gain‐of‐function Y792C mutant mGlu1 displayed enhanced constitutive activity in IP1 assays, which manifested as reduced orthosteric agonist activity. The mGlu1 PAMs restored glutamate potency in iCa2+ mobilisation for loss‐of‐function mutations and mGlu1 NAMs displayed enhanced inverse agonist activity at Y792C relative to wild‐type mGlu1.Conclusion and ImplicationsCollectively, these data highlight distinct mechanisms by which mGlu1 mutations affect receptor function and show allosteric modulators may present a therapeutic strategy to restore aberrant mGlu1 function in rare SCA subtypes.

项与 mGluR1 相关的新闻（医药）

2024-07-01

·PRNewswire

Finding the sweet spot in brain development

COLD SPRING HARBOR, N.Y., July 1, 2024 /PRNewswire/ -- Not everything in the brain is meant to last. As our brains assemble, trillions of neural connections have to be built or torn down at the right time and place. Otherwise, the seeds of disorders like autism can take root. Cold Spring Harbor Laboratory Assistant Professor Gabrielle Pouchelon studies how the brain is wired early in life. In doing so, she hopes to find the origins of various brain dysfunctions and new ways to treat them. Continue Reading A cross-section of the somatosensory cortex in a young mouse brain. A key receptor protein named mGluR1 (green) is necessary to prime sensory circuits early in life, affecting how the mouse senses the world through touch. In a new study, Pouchelon and her team zero in on a process known as pruning. This is when the brain removes unnecessary connections between neurons. The pruning of long-lasting connections is relatively well-known. Pouchelon's team focuses on special early connections that get cut to make way for long-lasting circuits in the mature brain. Though temporary, these early connections may play a critical role in shaping developing brain circuits. Pouchelon's lab has now discovered that a receptor protein named mGluR1 helps regulate the timing of these temporary connections in the mouse brain. Her team found that without mGluR1, neural connections stick around too long in the brain region that controls and processes touch via the whiskers. When the sensory circuit fails to mature properly, the mice demonstrate atypical behaviors. For example, they don't stand on their hind legs and sniff around the way other mice do. Importantly, the team notes that this critical step in circuit development occurs during the first week after birth. "The way the receptor works seems to be different than what has been described in adulthood," Pouchelon says. She explains: "In the context of neurodevelopmental disorders, that means when we try to target developmental defects, we could have a totally different therapeutic effect at different stages during development." Pouchelon's team hopes their discovery may serve as a guide for designing future therapeutics to treat brain dysfunction early. "The brain is a wonderful machine whose job is to adapt," says Dimitri Dumontier, the postdoc in Pouchelon's lab who co-led this study. "So, when you study neurodevelopmental disorders in adults or even teenagers, it is difficult to identify which mechanisms are causing the symptoms. That is why understanding early milestones of brain development is key." The hope is that by figuring out exactly how the brain matures, scientists can rescue this process early. This could help prevent symptoms of neurological disorders like autism from showing up in the first place. After all, the world is difficult enough to navigate as is. Pouchelon and Dumontier's work could someday help make life easier for countless young people. About Cold Spring Harbor Laboratory Founded in 1890, Cold Spring Harbor Laboratory has shaped contemporary biomedical research and education with programs in cancer, neuroscience, plant biology and quantitative biology. Home to eight Nobel Prize winners, the private, not-for-profit Laboratory employs 1,000 people including 600 scientists, students and technicians. For more information, visit SOURCE Cold Spring Harbor Laboratory

2024-06-07

·药渡

免疫细胞迁移

细胞迁移驱动肿瘤进展，特别是在癌症转移和逃逸，免疫细胞浸润等。由于大多数免疫疗法需要直接的细胞间接触，因此需要了解迁移以在治疗上增强抗肿瘤免疫细胞的浸润，同时阻断促肿瘤免疫细胞的募集。免疫细胞的肿瘤浸润受到癌细胞和免疫细胞的高度调控，因为癌细胞能够通过微环境进行免疫编辑，以增强促肿瘤免疫细胞定位并排斥抗肿瘤免疫细胞，进而使某些促肿瘤免疫细胞增强癌细胞的转移能力。细胞迁移模式趋化性和基底随机迁移（basal random migration）是免疫细胞和癌细胞迁移的两种主要迁移模式，受到完全不同分子信号通路的调节。 Annu. Rev. Biomed. Eng. 2022 趋化性包括沿邻近细胞产生的化学梯度的偏向定向迁移，是免疫细胞浸润肿瘤的基础。癌细胞可以调节免疫细胞募集，选择促肿瘤免疫细胞，包括髓源性抑制细胞（MDSC）和T调节细胞（Tregs），然后抑制免疫监视。趋化性也被癌细胞利用，特别是在转移过程中，因为可溶性因子和细胞外囊泡可以促进肿瘤细胞向侵入性边缘迁移并募集到继发性肿瘤部位。与趋化性相反，基底细胞随机迁移包括在没有化学梯度的情况下发生的无偏（随机，非定向）运动。基底细胞迁移通常发生在TME内，特别是在基质中，与血管和肿瘤之间的界面空间相比，可溶性因子的浓度往往更稳定，其中可溶性因子的梯度更陡峭。这些可溶性因子中的关键是细胞因子，尤其是趋化因子，通过趋化性驱动迁移。TME内免疫细胞的趋化和基底迁移描述了免疫细胞探索肿瘤以引发抗肿瘤或促肿瘤功能的程度。常用的趋化性实验（Annu. Rev. Biomed. Eng. 2022）常用的迁移实验（Annu. Rev. Biomed. Eng. 2022）巨噬细胞肿瘤相关巨噬细胞（TAM）在肿瘤相关免疫抑制中起关键作用。巨噬细胞可以通过其极化为M1或M2表型，来诱导炎症或免疫抑制。缺氧诱导TAMs释放可溶性因子，帮助将TME塑造成免疫抑制环境。例如，缺氧环境中的TAM释放更高水平的白细胞介素IL-6和IL-10，增加T细胞上的PD-1表达，以及更高水平的CCL17和CCL22，其诱导肿瘤Tregs。但最近的证据表明，缺氧在调节癌细胞（不仅是直接免疫细胞）以引发下游免疫抑制方面具有不同的作用。在缺氧条件下，黑色素瘤细胞分泌CCL2和集落刺激因子1水平升高的外泌体，将巨噬细胞极化为M2抗炎表型。 Transwell®测定显示，在常氧条件下，与来自黑色素瘤细胞的外泌体相比，来自缺氧黑色素瘤细胞的外泌体的巨噬细胞趋化性增强;这些缺氧外泌体以代谢依赖性方式将巨噬细胞推入M2表型。事实上，小鼠模型终点细胞富集实验（Endpoint cell enrichment assays）显示，缺氧性黑色素瘤肿瘤中存在的M2样细胞数量高于常氧黑色素瘤肿瘤。因此，缺氧肿瘤似乎促进巨噬细胞趋化性进入TME，诱导它们分化为前肿瘤M2表型，导致免疫抑制TME。然后，M2巨噬细胞通过分泌CCL22和CCL17来吸引另一类促肿瘤免疫细胞Tregs来加剧免疫抑制TME。 Annu. Rev. Biomed. Eng. 2022 中性粒细胞与巨噬细胞类似，中性粒细胞在癌症生物学中的作用是复杂的，可以促进和抑制肿瘤进展。三阴性乳腺癌（TNBC）患者肿瘤中的中性粒细胞与肿瘤生长减少相关。这种中性粒细胞抑制可能由TNBC细胞释放的趋化因子CXCL1和IL-8调节。代谢性谷氨酸受体1（mGluR1）在TNBC细胞上过表达，这种过表达导致TNBC细胞释放的CXCL1和IL-8下调。泛中性粒细胞浸润可能不会受到 TNBC 细胞的阻碍，但促肿瘤中性粒细胞会被选择性招募，而抗肿瘤中性粒细胞会被排斥。通过C3a / C3a受体轴，中性粒细胞可能优先募集到已转移的TNBC细胞的继发性肿瘤部位。携带已转移到肝脏的TNBC细胞小鼠模型显示，肝脏转移性TNBC细胞比肺转移性TNBC细胞分泌更高水平的C3a，表现出优先募集中性粒细胞募集。 T细胞 T细胞是免疫肿瘤学中研究最广泛的免疫细胞类型之一，但一个悬而未决的问题是如何增加CD8 + T细胞肿瘤浸润，人们认为这种T细胞亚型浸润到肿瘤核心，而不仅仅是沿着肿瘤边缘积累，可以改善患者的临床结果。了解TME阻碍细胞毒性T细胞浸润的机制可能改善T细胞免疫疗法。胶质瘤是免疫疗法具有挑战性的癌症类型之一，功能获得性IDH1突变是神经胶质瘤中最常见的突变之一。携带这种突变的患者表现出肿瘤浸润细胞毒性T细胞减少，与趋化因子CXCL10表达降低相关。卵巢癌是免疫疗法开发面临挑战的另一种癌症。卵巢癌细胞可以在表观遗传上沉默CCL5减少了CD8 + T细胞累积。树突状细胞存在不同的DC亚型。抗肿瘤DC亚群（如CD103 + DC）的肿瘤浸润可能导致更好的癌症预后，因为它们具有抗原呈递给T细胞的功能。然而，某些DC亚群，例如pre-DCs，可能是免疫抑制的，基质细胞衍生因子1（SDF-1）是卵巢癌细胞诱导DC趋化性的关键分泌因子。黑色素瘤是免疫疗法已被证明成功的癌症类型之一，尽管鉴于一些患者的抗肿瘤免疫细胞浸润程度低，仍有改进的余地。 β-catenin信号传导引起的黑色素瘤细胞分泌趋化因子CCL4减少，导致CD103 + DC肿瘤浸润受阻和CD103 + DC趋化性受阻。 Annu. Rev. Biomed. Eng. 2022 参考资料 Hsu BE, Roy J, Mouhanna J, Rayes RF, Ramsay L, et al. 2020. C3a elicits unique migratory responses in immature low-density neutrophils. Oncogene 39:2612–23 Phillip JM, Zamponi N, Phillip MP, Daya J, McGovern S, et al. 2021. Fractional re-distribution among cell motility states during ageing. Commun. Biol. 4:81 Wenxuan Du et al, Cell Trafficking at the Intersection of the Tumor–Immune Compartments，Annu. Rev. Biomed. Eng. 2022. 24:275–305

免疫疗法细胞疗法

2024-02-08

·生物探索

Nature | 钙感受器的双重游戏：揭秘其对G蛋白选择性和异构体调节的新机制

引言钙敏感受体(CaSR)是一个家族C的G蛋白偶联受体(GPCR)，在调节全身钙稳态中起核心作用。2024年2月7日，斯坦福大学Georgios Skiniotis团队（斯坦福大学Feng He、Cheng-Guo Wu、浙江大学高洋及哥本哈根大学Sabrina N. Rahman为该文章的共同第一作者）在Nature 在线发表题为“Allosteric modulation and G-protein selectivity of the Ca2+-sensing receptor”的研究论文，该研究使用冷冻电镜和功能分析来研究嵌入在脂质纳米盘中的人CaSR的激活及其在存在和不存在拟钙化药物cinacalcet的情况下与功能性Gi和Gq蛋白的偶联。高分辨率结构显示，Gi和Gq在活化的CaSR二聚体中驱动额外的构象变化，以稳定涉及关键蛋白-脂质相互作用的七跨膜结构域(7TM)的更广泛的不对称界面。受体的选择性Gi和Gq偶联是通过细胞内环2和C端的大量重排实现的，它们对两种G蛋白亚型的结合有不同的贡献，导致不同的CaSR-G蛋白界面。这些结构还揭示了天然多胺靶向CaSR上的多个位点，通过压缩两个原体之间带负电荷的区域来增强受体的激活。此外，该研究发现氨基酸l-色氨酸是一种众所周知的CaSR细胞外结构域的配体，它占据了G蛋白偶联原聚体的7TM束，与cinacalcet和其他变构调节剂位于同一位置。这些结果为CaSR对G蛋白的激活和选择性，以及内源性和外源性配体对其变构调节提供了一个框架。循环Ca2+水平的严格调节是人体生理的一个重要组成部分，它在很大程度上依赖于CaSR。该受体检测血清钙的升高并激活G蛋白信号，以限制甲状旁腺激素(PTH)的分泌并促进肾钙排泄。人类CaSR中数百种自然发生的突变导致各种疾病，包括家族性低钙血症/高钙血症1型、严重新生儿甲状旁腺功能亢进、常染色体显性低钙血症1型(ADH1)和5型巴特综合征。在影响全球近10%人口的慢性肾脏疾病患者中观察到CaSR的表达和激活降低。CaSR属于C家族GPCR，该家族还包括调节神经传递的γ-氨基丁酸B (GABAB)和代谢性谷氨酸(mGlu)受体(mGlu1-mGlu8)。家族C GPCR的功能是专性同源或异源二聚体，内源性配体参与远离膜平面的细胞外结构域(ECD)，通常包括一个配体结合的Venus flytrap结构域(VFT)，在大多数情况下，通过一个富含半胱氨酸的结构域(CRD)连接到特征7TM束。这个家族的成员表现出明显的G蛋白偶联选择性。mGlu1和mGlu5激活包括Gq/11在内的多种G蛋白，而其他mGlu受体优先激活Gi/o。另一方面，CaSR主要激活Gq/11和Gi/o亚型。早期对洗涤剂溶解mGlu2、mGlu4和GABAB的结构研究表明，C家族GPCR采用一种独特的机制与Gi偶联，涉及细胞内环的重组，而不打开7TM束。然而，目前尚不清楚这种机制是否适用于其他G蛋白亚型，以及C家族受体如何实现G蛋白的选择性。脂质纳米圆盘中活性态CaSR和CaSR -G蛋白复合物的冷冻电镜结构（Credit: Nature）CaSR的一个显著特征是它与多种天然配体结合，包括多价阳离子(如Ca2+)、阴离子(如磷酸、l -氨基酸、多肽和多胺)。这些配体在不同生理条件下相对浓度的变化可以促进或抑制受体的激活，因此CaSR似乎是一个微调的信号平台，整合各种化学输入来引发其生理作用。CaSR是由合成的阳性和阴性变构调节剂(PAM和NAMs)靶向治疗的，它们分别增强受体的激活或失活。例如，cinacalcet是FDA批准的靶向CaSR的PAM药物，用于治疗继发性甲状旁腺功能亢进和甲状旁腺癌。虽然已经报道了人类CaSR与不同配体(包括Ca2+， l -色氨酸(Trp)和PAM或NAMs)结合的冷冻电镜结构，但其他配体(如多胺)的结合模式尚未表征。该研究试图建立CaSR激活和G蛋白亚型偶联的丰富机制框架。在脂质纳米盘中重构的人类CaSR的冷冻电镜快照，以及功能数据的补充，揭示了CaSR如何利用由脂质和精胺分子稳定的不对称界面激活一个原聚体中的G蛋白；Gi和Gq如何参与采用不同构象的相同受体元件；7TM PAM细胞如何诱导侧链重排促进G蛋白偶联；天然氨基酸色氨酸可以在没有外源PAMs的情况下与7TM束结合。原文链接https://www.nature.com/articles/s41586-024-07055-2责编|探索君排版|探索君文章来源|“iNature”End往期精选围观一文读透细胞死亡(Cell Death) | 24年Cell重磅综述（长文收藏版）热文Science最新发布：全世界最前沿的125个科学问题热文Nature | 2024年值得关注的七项技术热文Nature | 自身免疫性疾病能被治愈吗？科学家们终于看到了希望热文Nature | 癌症与神经系统的致命舞蹈

细胞疗法