Edited and Reviewed by: Silvano Sozzani, Sapienza University of Rome, Italy
*Correspondence: Andreas H. Guse,
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Extracellular and intracellular adenine nucleotides (ANs) act as paracrine mediators or intracellular second messengers in almost all central processes in biology and medicine. They are essential for many (intra)cellular communication processes and are ubiquitously found in the plant and animal kingdoms. Many aspects of AN-governed or -modulated cell-cell communication and intracellular signaling are only partially known. Moreover, the physiological and pathological roles of ANs are only beginning to be understood. The Research Topic ‘
Intracellular signaling encompasses two broad areas, Ca2+ signaling evoked or modulated by ANs, and signaling by the intracellular second messenger 3’,5’-cyclic adenosine monophosphate (cAMP).
Ca2+ signaling often starts locally and, through several amplification mechanisms, subsequently turns into global signaling. Ca2+ microdomains are local Ca2+ signals that can be observed using high- or super-resolution microscopy imaging techniques. A review by Gil
In addition to Ca2+ signaling, which is known to be essential for T cell activation, cAMP is currently considered to be more of a negative intracellular regulator of T cell activation. The role of cAMP-metabolizing phosphodiesterases (cAMP-PDE) was reviewed by
Three papers are focused on the ATP-activated pro-inflammatory P2X receptor subtypes P2X4 and/or P2X7, and their role on immune cells.
Extracellular ANs are substrates of ectonucleotidases, nucleotide-metabolizing enzymes that are integrated into the cell membrane or attached to it. The enzymes can also be present in exosomes or as soluble enzymes in the extracellular fluid. They hydrolyze ANs by cleaving phosphoric acid ester groups. Depending on the subtype, ectonucleotidases convert ANs to other ANs, or form, at the end of the hydrolytic cascade, immunosuppressive, anti-inflammatory adenosine.
In their review article,
An original article by
Extracellular ATP, ADP, AMP, or NAD can be hydrolyzed by the orchestrated action of ectonucleotidases to ultimately produce adenosine, which triggers the activation of adenosine receptors (classified into four subtypes, A1, A2A, A2B, and A3). Extracellular adenosine regulates a wide range of physiological processes, such as the modulation of the immune system, with adenosine being mostly known as an immunosuppressive agent.
Several studies describe new methods and tools to study AN signaling and their targets in inflammation and immunity.
In addition to their being crucial in metabolic energy, ANs are pivotal mediators of both extracellular and intracellular signaling. Both the release of ATP or NAD and their conversion by ectoenzymes to AMP/adenosine activate purinergic receptor signaling. These and other signaling pathways are coupled to the intracellular generation of AN second messengers that regulate Ca2+ homeostasis and cell responses. The exact understanding and definition of the molecular cascade governing physiological and pathological processes (inflammation, neurodegeneration etc.), along with the characterization of the expression of AN-degrading enzymes and AN-sensitive receptors in different conditions, may offer the possibility to develop a therapeutic strategy and/or to identify new biomarkers (possibly also expressed on EV). This Research Topic presents interesting contributions that cover different aspects of this multifaceted AN-based signaling network.
AG: Writing – original draft, Writing – review & editing. CM: Writing – original draft, Writing – review & editing. SB: Writing – original draft, Writing – review & editing.
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