Extracellular adenosine activates AMP-dependent protein kinase (AMPK)

Area of Science:

• Cellular Metabolism
• Molecular Biology
• Biochemistry

Background:

• AMP-activated protein kinase (AMPK) regulates metabolic pathways based on cellular energy status.
• Traditionally, intracellular adenosine nucleotide pools are considered a consequence of altered energy metabolism.
• The role of extracellular adenosine in AMPK regulation remains largely unexplored.

Purpose of the Study:

• To investigate whether extracellular adenosine contributes to the regulation of AMPK signaling.
• To elucidate the mechanisms by which extracellular adenosine influences AMPK activity and downstream targets.

Main Methods:

• Utilized rat intestinal epithelial cell line (IEC-6) and liver parenchymal cell models.
• Administered adenosine and employed adenoviral vectors for dominant-negative inhibition of AMPK.
• Used 5'-iodotubercidine (5'-ITU) to inhibit adenosine kinase and formycin B to block CNT2 transporter activity.

Main Results:

• Extracellular adenosine rapidly increased intracellular AMP concentrations and upregulated alpha1AMPK in IEC-6 cells.
• Adenosine promoted phosphorylation of acetyl-CoA carboxylase (ACC), a key metabolic enzyme.
• Effects were blocked by dominant-negative AMPK, adenosine kinase inhibition (5'-ITU), and CNT2 transporter blockade (formycin B), indicating adenosine transport and phosphorylation are essential.

Conclusions:

• Extracellular adenosine, at physiological concentrations, activates AMPK and promotes ACC phosphorylation.
• Adenosine transport and subsequent intracellular phosphorylation are critical for its action on AMPK signaling.
• Nucleoside transporters represent potential novel regulators of AMPK and cellular energy metabolism.