Extracellular ATP and other nucleotides—ubiquitous triggers of intercellular messenger release

Abstract

Extracellular nucleotides, and ATP in particular, are cellular signal substances involved in the control of numerous (patho)physiological mechanisms. They provoke nucleotide receptor-mediated mechanisms in select target cells. But nucleotides can considerably expand their range of action. They function as primary messengers in intercellular communication by stimulating the release of other extracellular messenger substances. These in turn activate additional cellular mechanisms through their own receptors. While this applies also to other extracellular messengers, its omnipresence in the vertebrate organism is an outstanding feature of nucleotide signaling. Intercellular messenger substances released by nucleotides include neurotransmitters, hormones, growth factors, a considerable variety of other proteins including enzymes, numerous cytokines, lipid mediators, nitric oxide, and reactive oxygen species. Moreover, nucleotides activate or co-activate growth factor receptors. In the case of hormone release, the initially paracrine or autocrine nucleotide-mediated signal spreads through to the entire organism. The examples highlighted in this commentary suggest that acting as ubiquitous triggers of intercellular messenger release is one of the major functional roles of extracellular nucleotides. While initiation of messenger release by nucleotides has been unraveled in many contexts, it may have been overlooked in others. It can be anticipated that additional nucleotide-driven messenger functions will be uncovered with relevance for both understanding physiology and development of therapy.

Neurogenic Differentiation of Mesenchymal Stem Cells Induces Alterations in Extracellular Nucleotides Metabolism

“…Numerous ATP‐mediated processes are based on the signal amplification: release of ATP molecules stimulates the neighboring target cells (the same or different type) to propagate certain response. This mechanism underlies for example, the inflammatory reactions, hyperalgesia, migraine headache [Cieślak et al, ; Zimmermann, ]. According to our results, those previously published and described here, MSCs sense and interpret the ATP signaling in a different way.…”

“…The regulatory role of extracellular nucleotides, and ATP in particular, in physiological and pathological processes in adult nervous system is widely described and accepted [Burnstock, , , ; Bonan, ; Sperlagh and Illes, ; Cieślak et al, , ; Zimmermann, ]. Numerous ATP‐mediated processes are based on the signal amplification: release of ATP molecules stimulates the neighboring target cells (the same or different type) to propagate certain response.…”

Purinergic regulation of the immune system

“…ATP, UTP and other nucleotides can be released from apoptotic cells through pannexin 1 channels that are activated by caspase-mediated cleavage of the pannexin pore-associated carboxy-terminal autoinhibitory region 23 . ATP also can be released through additional cell-membrane channels, including other pannexins, connexins, maxichannels and P2X 7 R pores 22 . As these nucleo tides are chemoattractants, they have been referred to as 'find me' signals 5 that attract phagocytes, activate platelets and stimulate local endothelial nitric oxide synthase (eNOS)-dependent vasodilation.…”

The Role of Nucleotides in Glial Cells during Peripheral Nerve Trauma and Compressive Disorders

“…The regulation of the increase of other substances in cells, glucose and urea metabolism, and participation in inflammatory response processes are among these mechanisms [33,34].…”