Journal article
Loss of α-cell GRK2 modulates glucagon response and supports cardiac function
Molecular pharmacology, v 108(4), 100115
01 Apr 2026
PMID: 41895229
Featured in Collection : Drexel's Newest Publications
Abstract
Pancreatic alpha-cells secrete glucagon to maintain glucose homeostasis, yet the molecular mechanisms regulating hormone release are understudied. G-protein coupled receptor kinases (GRKs) regulate receptor desensitization; however, their role in alpha-cells remains unknown. Here, we generated an inducible alpha-cell-specific GRK2 knockout (alpha GRK2KO) mouse model to investigate the role of GRK2 in islet physiology, systemic metabolism, and cardiac function. Loss of GRK2 in alpha-cells reduced islet GRK2 protein by similar to 20%, consistent with alpha-cell islet abundance, and produced negligible alterations in glucose tolerance without affecting insulin secretion. Notably, alpha GRK2KO mice had altered fast/fed glucagon responses, reduced adiposity, and lower body weight. Despite minimal effects on systemic glucose handling, alpha GRK2KO animals exhibited improved cardiac function, characterized by enhanced ejection fraction and fractional shortening, without signs of hypertrophy. High-fat, high-sucrose diet feeding abated these changes, underscoring the diet-dependent impact of alpha-cell GRK2. Together, these findings identify GRK2 as a previously unrecognized regulator of alpha-cell glucagon secretion that influences systemic energy balance and cardiac performance through endocrine crosstalk. This work establishes a framework for alpha-cell G protein-coupled receptor regulation and highlights GRK2 as a potential therapeutic node linking islet function, metabolism, and the heart. Significance Statement: This study explores the role of GRK2 in alpha-cell biology as a regulator of glucagon dynamics and cardiac function, thereby establishing a new endocrine link between islet signaling and cardiac biology.
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Details
- Title
- Loss of α-cell GRK2 modulates glucagon response and supports cardiac function
- Creators
- Jonathan Snyder (Corresponding Author) - Drexel University, Pharmacology and PhysiologyLilly Underwood - University of Alabama at BirminghamChun-sun Jiang - University of Alabama at BirminghamVictoria Kaml - University of Alabama at BirminghamSnekha Rajasekaran - University of Alabama at BirminghamLily Xie - University of Alabama at BirminghamC. Reid Dotson - University of Alabama at BirminghamPriscila Y. Sato - Univ Alabama Birmingham, Dept Med, Div Cardiovasc Dis, Birmingham, AL USA
- Publication Details
- Molecular pharmacology, v 108(4), 100115
- Conference
- The 2024 ASPET Julius Axelrod Symposium: Novel Insights into G Protein-Coupled Receptor Kinases Modifying Cardiac Function and Metabolism (The symposium featured curated articles on GPCR kinases modifying cardiac metabolism, rather than a single in-person physical location in 2024)
- Publisher
- Elsevier
- Number of pages
- 8
- Grant note
- R01HL163666; R56HL149887 / National Institute of Health; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA
- Resource Type
- Journal article
- Language
- English
- Academic Unit
- Pharmacology and Physiology
- Web of Science ID
- WOS:001731204500001
- Scopus ID
- 2-s2.0-105034674103
- Other Identifier
- 991022172971804721