---
title: "GRK2 phosphorylation of AdipoR1 Ser205 drives diabetic cardiomyopathy; S205A mutation restores adi"
id: "pubmed-42763212"
canonical_url: "https://medichelpline.com/clinical-feed/pubmed-42763212"
content_type: "clinical_feed_article"
specialty: "Pharmacology"
source_name: "PubMed / NCBI"
source_url: "https://pubmed.ncbi.nlm.nih.gov/42763212/"
doi: "10.3760/cma.j.cn112137-20260508-01227"
published_at: "2026-09-22T00:00:00.000Z"
evidence_level: "English Abstract"
license: "CC-BY-NC-4.0 / Informational Use"
---
# GRK2 phosphorylation of AdipoR1 Ser205 drives diabetic cardiomyopathy; S205A mutation restores adi
## Provenance & Clinical Metadata
- **Canonical URL:** https://medichelpline.com/clinical-feed/pubmed-42763212
- **Specialty:** [Pharmacology](https://medichelpline.com/clinical-feed/pharmacology.md)
- **Primary Source:** PubMed / NCBI
- **Source URL:** [Original Journal Publication](https://pubmed.ncbi.nlm.nih.gov/42763212/)
- **DOI:** [10.3760/cma.j.cn112137-20260508-01227](https://doi.org/10.3760%2Fcma.j.cn112137-20260508-01227)
- **Published At:** 2026-09-22T00:00:00.000Z
- **Evidence Rating:** English Abstract
## Executive GIST (TL;DR)
- The study investigated the role of G-protein coupled receptor kinase 2 (**GRK2**)-mediated phosphorylation of adiponectin receptor 1 (**AdipoR1**) at serine 205 (**Ser205**) in diabetic cardiomyopathy (**DCM**) and tested whether site-directed mutation (S205A) rescues adiponectin (**APN**) signaling. - A DCM model was created in C57BL/6J mice by high-fat diet plus streptozotocin (HFD+STZ). DCM mice had higher blood glucose, triglycerides, LDL-cholesterol and **APN**, impaired diastolic function, increased myocardial fibrosis, and elevated myocardial **GRK2** and phosphorylated serine (p-Ser) levels versus controls. - Co-immunoprecipitation showed reduced binding of adaptor protein **APPL1** to **AdipoR1** in myocardial tissue from DCM mice, and APN-stimulated **AMPK/Akt** phosphorylation was blunted in primary cardiomyocytes from DCM mice. - In AdipoR1-knockout neonatal cardiomyocytes, overexpression and site-directed mutation experiments compared wild-type AdipoR1 (AdipoR1WT) and Ser205-to-alanine mutant (AdipoR1S205A) with or without **GRK2** overexpression. The S205A mutation restored APN-induced **p-AMPK/AMPK** and **p-Akt/Akt** ratios and preserved AdipoR1–APPL1 interaction despite GRK2. - In vivo AAV9 delivery of AdipoR1S205A to AdipoR1-knockout mice subjected to DCM induction and APN infusion produced improved diastolic function (higher E/A ratio, rRSR, LSR, rLSR) and reduced myocardial fibrosis versus AAV9-AdipoR1WT+DCM. - Overall, **GRK2**-mediated phosphorylation at **AdipoR1 Ser205** disrupts APN–AdipoR1 signaling by decoupling **APPL1**, contributing to aggravated cardiac dysfunction in DCM. Targeted inhibition of Ser205 phosphorylation via **site-directed mutagenesis** restores downstream **AMPK/Akt** signaling and ameliorates cardiac outcomes in this mouse model.
## Clinical Analysis & Structured Key Points
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[ Full text links ](https://pubmed.ncbi.nlm.nih.gov/42763212/) ### Actions Cite Collections Add to Collections * Create a new collection * Add to an existing collection Name your collection: Name must be less than 100 characters Choose a collection: Unable to load your collection due to an error [Please try again](https://pubmed.ncbi.nlm.nih.gov/42763212/) Add Cancel Permalink Permalink Copy Display options Display options Format Abstract PubMed PMID ### Page navigation * [ Title & authors ](https://pubmed.ncbi.nlm.nih.gov/42763212/#heading) * [ Abstract ](https://pubmed.ncbi.nlm.nih.gov/42763212/#abstract) * [ Conflict of interest statement ](https://pubmed.ncbi.nlm.nih.gov/42763212/#conflict-of-interest) * [ Publication types ](https://pubmed.ncbi.nlm.nih.gov/42763212/#publication-types) * [ MeSH terms ](https://pubmed.ncbi.nlm.nih.gov/42763212/#mesh-terms) * [ Substances ](https://pubmed.ncbi.nlm.nih.gov/42763212/#substances) * [ Grants and funding ](https://pubmed.ncbi.nlm.nih.gov/42763212/#grants) * [ LinkOut - more resources ](https://pubmed.ncbi.nlm.nih.gov/42763212/#linkout) Title & authors Abstract Conflict of interest statement Publication types MeSH terms Substances Grants and funding LinkOut - more resources Zhonghua Yi Xue Za Zhi Actions * [ Search in PubMed ](https://pubmed.ncbi.nlm.nih.gov/?term=%22Zhonghua+Yi+Xue+Za+Zhi%22%5Bjour%5D&sort=date&sort_order=desc) * [ Search in NLM Catalog ](https://www.ncbi.nlm.nih.gov/nlmcatalog?term=%22Zhonghua+Yi+Xue+Za+Zhi%22%5BTitle+Abbreviation%5D) * [ Add to Search ](https://pubmed.ncbi.nlm.nih.gov/42763212/) . 2026 Sep 22;106(35):3772-3781. doi: 10.3760/cma.j.cn112137-20260508-01227. # [Mechanism of GRK2-mediated AdipoR1 Ser205 phosphorylation in myocardial injury in diabetic mice and the cardioprotective effect of site-directed mutagenesis] [Article in Chinese] [Z J Yang](https://pubmed.ncbi.nlm.nih.gov/?term=Yang+ZJ&cauthor_id=42763212)[ 1 ](https://pubmed.ncbi.nlm.nih.gov/42763212/#full-view-affiliation-1 "Air Force Clinical College, Anhui Medical University, Hefei 230032, China."), [S C Hu](https://pubmed.ncbi.nlm.nih.gov/?term=Hu+SC&cauthor_id=42763212)[ 2 ](https://pubmed.ncbi.nlm.nih.gov/42763212/#full-view-affiliation-2 "Clinical Medicine Laboratory, Department of Research, Air Force Medical Center, Beijing 100142, China."), [D Zhu](https://pubmed.ncbi.nlm.nih.gov/?term=Zhu+D&cauthor_id=42763212)[ 3 ](https://pubmed.ncbi.nlm.nih.gov/42763212/#full-view-affiliation-3 "Department of Endocrinology, Air Force Medical Center, Beijing 100142, China."), [Z Y Zhang](https://pubmed.ncbi.nlm.nih.gov/?term=Zhang+ZY&cauthor_id=42763212)[ 3 ](https://pubmed.ncbi.nlm.nih.gov/42763212/#full-view-affiliation-3 "Department of Endocrinology, Air Force Medical Center, Beijing 100142, China."), [Y F Kang](https://pubmed.ncbi.nlm.nih.gov/?term=Kang+YF&cauthor_id=42763212)[ 3 ](https://pubmed.ncbi.nlm.nih.gov/42763212/#full-view-affiliation-3 "Department of Endocrinology, Air Force Medical Center, Beijing 100142, China."), [Y M Tian](https://pubmed.ncbi.nlm.nih.gov/?term=Tian+YM&cauthor_id=42763212)[ 3 ](https://pubmed.ncbi.nlm.nih.gov/42763212/#full-view-affiliation-3 "Department of Endocrinology, Air Force Medical Center, Beijing 100142, China."), [L Zhang](https://pubmed.ncbi.nlm.nih.gov/?term=Zhang+L&cauthor_id=42763212)[ 3 ](https://pubmed.ncbi.nlm.nih.gov/42763212/#full-view-affiliation-3 "Department of Endocrinology, Air Force Medical Center, Beijing 100142, China."), [Q Ye](https://pubmed.ncbi.nlm.nih.gov/?term=Ye+Q&cauthor_id=42763212)[ 2 ](https://pubmed.ncbi.nlm.nih.gov/42763212/#full-view-affiliation-2 "Clinical Medicine Laboratory, Department of Research, Air Force Medical Center, Beijing 100142, China."), [L M Fang](https://pubmed.ncbi.nlm.nih.gov/?term=Fang+LM&cauthor_id=42763212)[ 2 ](https://pubmed.ncbi.nlm.nih.gov/42763212/#full-view-affiliation-2 "Clinical Medicine Laboratory, Department of Research, Air Force Medical Center, Beijing 100142, China.") Affiliations Expand ### Affiliations * 1 Air Force Clinical College, Anhui Medical University, Hefei 230032, China. * 2 Clinical Medicine Laboratory, Department of Research, Air Force Medical Center, Beijing 100142, China. * 3 Department of Endocrinology, Air Force Medical Center, Beijing 100142, China. * PMID: **42763212** * DOI: [ 10.3760/cma.j.cn112137-20260508-01227 ](https://doi.org/10.3760/cma.j.cn112137-20260508-01227) Item in Clipboard # [Mechanism of GRK2-mediated AdipoR1 Ser205 phosphorylation in myocardial injury in diabetic mice and the cardioprotective effect of site-directed mutagenesis] [Article in Chinese] Z J Yang et al. Zhonghua Yi Xue Za Zhi. 2026. Show details Display options Display options Format Abstract PubMed PMID Zhonghua Yi Xue Za Zhi Actions * [ Search in PubMed ](https://pubmed.ncbi.nlm.nih.gov/?term=%22Zhonghua+Yi+Xue+Za+Zhi%22%5Bjour%5D&sort=date&sort_order=desc) * [ Search in NLM Catalog ](https://www.ncbi.nlm.nih.gov/nlmcatalog?term=%22Zhonghua+Yi+Xue+Za+Zhi%22%5BTitle+Abbreviation%5D) * [ Add to Search ](https://pubmed.ncbi.nlm.nih.gov/42763212/) . 2026 Sep 22;106(35):3772-3781. doi: 10.3760/cma.j.cn112137-20260508-01227. ### Authors [Z J Yang](https://pubmed.ncbi.nlm.nih.gov/?term=Yang+ZJ&cauthor_id=42763212)[ 1 ](https://pubmed.ncbi.nlm.nih.gov/42763212/#short-view-affiliation-1 "Air Force Clinical College, Anhui Medical University, Hefei 230032, China."), [S C Hu](https://pubmed.ncbi.nlm.nih.gov/?term=Hu+SC&cauthor_id=42763212)[ 2 ](https://pubmed.ncbi.nlm.nih.gov/42763212/#short-view-affiliation-2 "Clinical Medicine Laboratory, Department of Research, Air Force Medical Center, Beijing 100142, China."), [D Zhu](https://pubmed.ncbi.nlm.nih.gov/?term=Zhu+D&cauthor_id=42763212)[ 3 ](https://pubmed.ncbi.nlm.nih.gov/42763212/#short-view-affiliation-3 "Department of Endocrinology, Air Force Medical Center, Beijing 100142, China."), [Z Y Zhang](https://pubmed.ncbi.nlm.nih.gov/?term=Zhang+ZY&cauthor_id=42763212)[ 3 ](https://pubmed.ncbi.nlm.nih.gov/42763212/#short-view-affiliation-3 "Department of Endocrinology, Air Force Medical Center, Beijing 100142, China."), [Y F Kang](https://pubmed.ncbi.nlm.nih.gov/?term=Kang+YF&cauthor_id=42763212)[ 3 ](https://pubmed.ncbi.nlm.nih.gov/42763212/#short-view-affiliation-3 "Department of Endocrinology, Air Force Medical Center, Beijing 100142, China."), [Y M Tian](https://pubmed.ncbi.nlm.nih.gov/?term=Tian+YM&cauthor_id=42763212)[ 3 ](https://pubmed.ncbi.nlm.nih.gov/42763212/#short-view-affiliation-3 "Department of Endocrinology, Air Force Medical Center, Beijing 100142, China."), [L Zhang](https://pubmed.ncbi.nlm.nih.gov/?term=Zhang+L&cauthor_id=42763212)[ 3 ](https://pubmed.ncbi.nlm.nih.gov/42763212/#short-view-affiliation-3 "Department of Endocrinology, Air Force Medical Center, Beijing 100142, China."), [Q Ye](https://pubmed.ncbi.nlm.nih.gov/?term=Ye+Q&cauthor_id=42763212)[ 2 ](https://pubmed.ncbi.nlm.nih.gov/42763212/#short-view-affiliation-2 "Clinical Medicine Laboratory, Department of Research, Air Force Medical Center, Beijing 100142, China."), [L M Fang](https://pubmed.ncbi.nlm.nih.gov/?term=Fang+LM&cauthor_id=42763212)[ 2 ](https://pubmed.ncbi.nlm.nih.gov/42763212/#short-view-affiliation-2 "Clinical Medicine Laboratory, Department of Research, Air Force Medical Center, Beijing 100142, China.") ### Affiliations * 1 Air Force Clinical College, Anhui Medical University, Hefei 230032, China. * 2 Clinical Medicine Laboratory, Department of Research, Air Force Medical Center, Beijing 100142, China. * 3 Department of Endocrinology, Air Force Medical Center, Beijing 100142, China. * PMID: **42763212** * DOI: [ 10.3760/cma.j.cn112137-20260508-01227 ](https://doi.org/10.3760/cma.j.cn112137-20260508-01227) Item in Clipboard Full text links Cite Display options Display options Format Abstract PubMed PMID ## Abstract in [ English, ](https://pubmed.ncbi.nlm.nih.gov/42763212/#eng-abstract) [ Chinese ](https://pubmed.ncbi.nlm.nih.gov/42763212/#zho-abstract) **Objective:** To explore the role and mechanism of G-protein coupled receptor kinase 2 (GRK2)-mediated phosphorylation of adiponectin receptor 1 (AdipoR1) in diabetic cardiomyopathy (DCM), and to verify the therapeutic effect of site-directed mutagenesis targeting serine at position 205 (Ser205) of AdipoR1. **Methods:** Twenty 4-week-old C57BL/6J mice were randomly assigned to the normal control (NC) group and the DCM model group using a random-number table, with 10 mice per group. The DCM model was established in the DCM group by high-fat diet (HFD) feeding combined with intraperitoneal injection of streptozotocin (STZ). After 21-week intervention, 6 mice from each group were selected using a random-number table for measurements of serum biochemical parameters, adiponectin (APN) levels and cardiac diastolic function. Following euthanasia, myocardial tissues were harvested for Masson's trichrome staining to evaluate the degree of myocardial fibrosis. Co-immunoprecipitation and Western blot (WB) assays were performed to determine GRK2 expression, phosphorylated serine (p-Ser) levels, and the binding capacity between AdipoR1 and adaptor protein, phosphotyrosine-binding domain and leucine zipper motif 1 (APPL1). The remaining 4 mice per group were used for isolation of primary adult cardiomyocytes, which were treated with exogenous APN or phosphate-buffered saline (PBS). Phosphorylation status of the downstream adenosine monophosphate-activated protein kinase (AMPK)/protein kinase B (Akt) signaling pathway was subsequently detected. Twenty-eight 3-day-old AdipoR1-knockout neonatal mice were included in further experiments. Four of these AdipoR1-knockout neonatal mice were randomly selected by a random-number table to isolate primary cardiomyocytes. Plasmid co-transfection was conducted to assess AdipoR1-APPL1 interaction and downstream AMPK/Akt phosphorylation upon GRK2 overexpression. Four experimental subgroups were set: Adenovirus-empty(Ad-empty)+3×Flag-AdipoR1WT, Ad-empty+3×Flag-AdipoR1S205A, adenovirus-mediated GRK2(Ad-GRK2)+3×Flag-AdipoR1WT, and Ad-GRK2+3×Flag-AdipoR1S205A. This experiment aimed to identify whether Ser205 phosphorylation serves as the key molecular event whereby GRK2 blocks APN signaling. From the remaining 24 AdipoR1-knockout neonatal mice, 12 were randomly allocated into two groups (6 mice per group) using a random-number table. On postnatal day 3, mice received an injection of either adeno-associated virus serotype 9 (AAV9)-AdipoR1WT or AAV9-AdipoR1S205A. Ten weeks later, primary adult cardiomyocytes were isolated and divided into 4 subgroups: AAV9-AdipoR1WT+Ad-empty, AAV9-AdipoR1WT+Ad-GRK2, AAV9-AdipoR1S205A+Ad-empty, and AAV9-AdipoR1S205A+Ad-GRK2. GRK2 was overexpressed in vitro, and immunofluorescence co-localization was applied to quantify the co-localization of AdipoR1 and APPL1. The leftover 12 AdipoR1-knockout neonatal mice were randomized into two groups (6 mice per group) with a random-number table, and injected with the aforementioned viruses on postnatal day 3. Four weeks after virus injection, DCM was induced by HFD plus STZ administration, yielding two in-vivo groups: AAV9-AdipoR1WT+DCM (wild-type group) and AAV9-AdipoR1S205A+DCM (point-mutation group). APN was continuously delivered via osmotic minipumps. Eight weeks after APN intervention, cardiac function and myocardial fibrosis were evaluated. **Results:** In C57BL/6J mice, the DCM group exhibited significantly higher levels of blood glucose, triglycerides, low-density lipoprotein-cholesteral and adiponectin (APN) compared with the NC group (all _P_ <0.001). Statistically significant differences were observed between the two groups in the E/A ratio, radial strain rate, reverse radial strain rate (rRSR), longitudinal strain rate (LSR), and reverse longitudinal strain rate (rLSR) (all _P_ <0.05). The fraction of myocardial fibrotic area was larger in the DCM group than in the NC group (9.20±1.66 vs 1.24±0.51, _P_ <0.001). Myocardial protein levels of GRK2 (4.81±0.46 vs 1.03±0.09, _P_ <0.001) and p-Ser (1.75±0.21 vs 0.98±0.05, _P_ <0.001) were elevated in the DCM group relative to the NC group. The binding ratio of APPL1 to AdipoR1 in myocardial tissue was decreased in the DCM group versus the NC group (0.398±0.085 vs 0.978±0.088, _P_ <0.001). APN-stimulated AMPK/Akt phosphorylation was blunted in primary adult cardiomyocytes isolated from DCM-model C57BL/6J mice. In-vitro experiments using AdipoR1-knockout neonatal mouse cardiomyocytes demonstrated that following AdipoR1 Ser205 site mutation, the ratios of p-AMPK/AMPK (4.025±0.767 vs 1.003±0.087, _P_ <0.001) and p-Akt/Akt (4.125±0.544 vs 0.990±0.034, _P_ <0.001) were markedly increased in the 3×Flag-AdipoR1S205A+APN group compared with the 3×Flag-AdipoR1S205A+PBS group. In primary adult cardiomyocytes derived from AdipoR1-knockout mice, the AAV9-AdipoR1S205A+Ad-GRK2 group restored the AdipoR1-APPL1 interaction in the presence of GRK2 when compared with the AAV9-AdipoR1WT+Ad-GRK2 group (_P_ =0.014). In the in-vivo DCM model established in AdipoR1-knockout mice, the AAV9-AdipoR1S205A+DCM group displayed higher E/A ratio, rRSR, LSR and rLSR values, together with a lower myocardial fibrotic area fraction (all _P_ <0.05), relative to the AAV9-AdipoR1WT+DCM group. **Conclusions:** GRK2-mediated phosphorylation of AdipoR1 at serine 205 triggers APN-AdipoR1 metabolic dysfunction, which represents a critical contributor to aggravated cardiac dysfunction in DCM. This mechanism is associated with the decoupling of AdipoR1 from APPL1. Targeted inhibition of AdipoR1 phosphorylation via site-directed mutagenesis restores APN-AdipoR1 signaling and ameliorates cardiac dysfunction in DCM. **目的：** 探索G蛋白偶联受体激酶2（GRK2）介导的脂联素受体1（AdipoR1）第205位丝氨酸（Ser205）磷酸化在糖尿病小鼠心肌损伤中的作用机制及定点突变技术的心肌保护效应。 **方法：** 采用随机数字表法将20只4周龄C57BL/6J小鼠随机分为正常对照（NC）组与糖尿病心肌病（DCM）模型组，每组各10只。DCM模型组通过高脂饮食（HFD）联合链脲佐菌素（STZ）腹腔注射方式建立DCM模型。干预21周后采用随机数字表法每组各取6只小鼠检测血清生化指标、脂联素（APN）水平及心脏舒张功能，处死后取心肌组织行马松三色染色评估心肌纤维化程度，并采用免疫共沉淀及蛋白质印迹（WB）法检测GRK2表达、磷酸化丝氨酸（p-Ser）及AdipoR1-磷酸酪氨酸结合结构域与亮氨酸拉链模体的衔接蛋白1（APPL1）结合能力；剩余每组各4只（共8只）C57BL/6J小鼠，分离成年小鼠原代心肌细胞，分别给予外源性APN或磷酸盐缓冲液（PBS）处理，检测下游腺苷酸活化蛋白激酶（AMPK）/蛋白激酶B（Akt）信号通路磷酸化水平。另取3日龄AdipoR1敲除小鼠乳鼠28只，采用随机数字表法随机选取4只AdipoR1敲除小鼠乳鼠分离原代心肌细胞，通过质粒共转染的方法检测GRK2过表达时的AdipoR1-APPL1结合及下游AMPK/Akt信号磷酸化水平［分为4组：空腺病毒载体（Ad-empty）+3×Flag-AdipoR1WT组、Ad-empty+3×Flag-AdipoR1S205A组、腺病毒载体介导的GRK2（Ad-GRK2）+3×Flag-AdipoR1WT组、Ad-GRK2+3×Flag-AdipoR1S205A组］，明确Ser205位点磷酸化是GRK2阻断APN信号传导的关键分子事件；采用随机数字表法从剩余的24只AdipoR1敲除小鼠乳鼠中随机选取12只AdipoR1敲除小鼠乳鼠，随机分为两组，每组各6只，出生第3天分别注射9型腺相关病毒（AAV9）-AdipoR1WT或AAV9-AdipoR1S205A病毒，10周后分离成年小鼠原代心肌细胞（分为4组：AAV9-AdipoR1WT+Ad-empty组、AAV9-AdipoR1WT+Ad-GRK2组、AV9-AdipoR1S205A+Ad-empty组、AAV9-AdipoR1S205A+Ad-GRK2组），体外过表达GRK2，通过免疫荧光共定位检测AdipoR1与APPL1共定位水平；采用随机数字表法将剩余的12只AdipoR1敲除小鼠乳鼠随机分为两组，每组各6只，出生第3天分别注射上述病毒，4周后通过HFD联合STZ建立DCM模型，分为AAV9-AdipoR1WT+DCM组（野生组）、AAV9-AdipoR1S205A+D
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