N6-methyladenosine (m6A) is an endogenous A3 adenosine receptor ligand

About 150 post-transcriptional RNA modifications have been identified in all kingdoms of life. During RNA catabolism, most modified nucleosides are resistant to degradation and are released into the extracellular space. In this study, we explored the physiological role of these extracellular modified nucleosides and found that N-6-methyladenosine (m(6)A), widely recognized as an epigenetic mark in RNA, acts as a ligand for the human adenosine A3 receptor, for which it has greater affinity than unmodified adenosine. We used structural modeling to define the amino acids required for specific binding of m(6)A to the human A3 receptor. We also demonstrated that m(6)A was dynamically released in response to cytotoxic stimuli and facilitated type I allergy in vivo. Our findings implicate m(6)A as a signaling molecule capable of activating G protein-coupled receptors (GPCRs) and triggering pathophysiological responses, a previously unreported property of RNA modifications.

Automated summary

The study identified N-6-methyladenosine (m(6)A) as a ligand for the human adenosine A3 receptor with higher affinity than unmodified adenosine. Structural modeling revealed the amino acids required for specific binding of m(6)A to the human A3 receptor and demonstrated its dynamic release in response to cytotoxic stimuli and facilitation of type I allergy in vivo. These findings suggest m(6)A as a signaling molecule capable of activating G protein-coupled receptors (GPCRs) and triggering pathophysiological responses, a previously unreported property of RNA modifications.