Receptor-specific adenosine signalling governs astrocyte glycogen homeostasis

Belko Parkel, Kaja (author), Gržina, Živa Tajda (author), Zorec, Robert (author), Marko, Kreft (author)

Adenosine in the brain rises with metabolic load and signals through A1, A2A, A2B, and A3 receptors, but how individual subtypes regulate astrocytic energy metabolism remains incompletely defined. We combined live-cell FRET sensors for glucose, lactate, and cAMP with Ca²⁺ imaging in primary rat astrocytes to dissect receptor-specific actions. We probed receptor contributions using adenosine and selective agonists (CCPA, A1; CGS21680, A2A; BAY 60-6583, A2B). Glycogen content was quantified by periodic acid-Schiff (PAS) staining after acute stimulation and during recovery from glucose deprivation. Adenosine increased intracellular glucose concentration. Among subtypes, A2B activation reproduced this effect, whereas A1 and A2A did not. However, in glucose-free extracellular solution, adenosine and A2B activation elevated intracellular glucose, implicating glycogenolysis. PAS analysis showed that A2A and A2B increased perinuclear glycogen, with A2B also increasing peripheral glycogen. During recovery from glucose deprivation, adenosine and A2B receptor agonists slowed glycogen replenishment, whereas A2A agonists enhanced perinuclear stores. cAMP concentration rose with A2A and A2B receptor stimulation and after A1 antagonism, but not with adenosine itself, consistent with balanced A1/A2 co-activation. Ca²⁺ responses were transient for adenosine/A1 and sustained for A2A/A2B. Selective A2B activation produced a significant increase in intracellular lactate compared with vehicle. Together, these data identify A2B signalling as a principal driver of acute glucose mobilisation while slowing glycogen replenishment in astrocytes, operating through cAMP elevation and sustained Ca²⁺ signals, whereas A2A preferentially promotes perinuclear glycogen accumulation.

• Language: English
• Keywords: A2B adenosine receptor, A2A adenosine receptor, glycogen homeostasis, lactate metabolism, astrocytes
• Work type: Article
• Typology: 1.01 - Original Scientific Article
• Organization: BF - Biotechnical Faculty; MF - Faculty of Medicine
• Publication status: Published
• Publication version: Version of Record
• Publication date: 19.02.2026
• Year: 2027
• Number of pages: 20 str.
• Numbering: Vol. 18, iss. 2
• PID: 20.500.12556/RUL-179642
• eISSN: 2152-5250
• DOI: 10.14336/AD.2025.1389
• Publication date in RUL: 19.02.2026

Record is a part of a journal

• Title: Aging and Disease
• Publisher: Aging and Disease
• Year: 2027
• ISSN: 2152-5250

Licences

• License: CC BY 4.0, Creative Commons Attribution 4.0 International
• Link: http://creativecommons.org/licenses/by/4.0/
• Description: This is the standard Creative Commons license that gives others maximum freedom to do what they want with the work as long as they credit the author.

Secondary language

• Language: Slovenian
• Keywords: adenozinski receptor A2B, adenozinski receptor A2A, homeostaza glikogena, presnova laktata, astrociti