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Review
. 2024 Jan 18:11:1343653.
doi: 10.3389/fcell.2023.1343653. eCollection 2023.

Extracellular ATP/adenosine dynamics in the brain and its role in health and disease

Eiji Shigetomi  1   2 , Kent Sakai  1   2 , Schuichi Koizumi  1   2
Affiliations
Review

Extracellular ATP/adenosine dynamics in the brain and its role in health and disease

Eiji Shigetomi et al. Front Cell Dev Biol. .

Abstract

Extracellular ATP and adenosine are neuromodulators that regulate numerous neuronal functions in the brain. Neuronal activity and brain insults such as ischemic and traumatic injury upregulate these neuromodulators, which exert their effects by activating purinergic receptors. In addition, extracellular ATP/adenosine signaling plays a pivotal role in the pathogenesis of neurological diseases. Virtually every cell type in the brain contributes to the elevation of ATP/adenosine, and various mechanisms underlying this increase have been proposed. Extracellular adenosine is thought to be mainly produced via the degradation of extracellular ATP. However, adenosine is also released from neurons and glia in the brain. Therefore, the regulation of extracellular ATP/adenosine in physiological and pathophysiological conditions is likely far more complex than previously thought. To elucidate the complex mechanisms that regulate extracellular ATP/adenosine levels, accurate methods of assessing their spatiotemporal dynamics are needed. Several novel techniques for acquiring spatiotemporal information on extracellular ATP/adenosine, including fluorescent sensors, have been developed and have started to reveal the mechanisms underlying the release, uptake and degradation of ATP/adenosine. Here, we review methods for analyzing extracellular ATP/adenosine dynamics as well as the current state of knowledge on the spatiotemporal dynamics of ATP/adenosine in the brain. We focus on the mechanisms used by neurons and glia to cooperatively produce the activity-dependent increase in ATP/adenosine and its physiological and pathophysiological significance in the brain.

Keywords: ATP; adenosine; astrocytes; genetically encoded sensors; microglia; neurological disease; purinergic receptor; seizure.

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

FIGURE 1
FIGURE 1
Purinergic signaling regulated by neurons and glia. Neurons and glia communicate with each other using purinergic signaling. Virtually every type of cell can release, receive, and contribute to purinergic signaling; therefore, the timing and location of these events are important. The cartoons show proposed models of how purinergic signaling modulates neuron-glia communication in the brain. (A) Neurons release ATP from presynaptic terminals and adenosine from postsynaptic sites in an activity-dependent manner. Adenosine activate A1 receptor to inhibit synaptic transmission and to hyperpolarize neurons. (B) Astrocytes release ATP in response to several stimuli including neuronal activities. Astrocytic ATP is converted to adenosine activating presynaptic A1 receptor to inhibit synaptic transmission. Astrocytes can release ATP through multiple pathways. (C) Neuronal ATP activate P2Y12 receptors in microglial processes. The ATP is converted to adenosine to decrease neuronal excitability via A1 receptor. (D) Neuronal (D1) or astrocytic (D2) ATP activates P2Y12 receptors in microglial processes. Microglia, in turn, send protective signals to neurons (D1) or astrocytes (D2).
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Grants and funding

The author(s) declare financial support was received for the research, authorship, and/or publication of this article. ES was supported by JSPS Grants-in-Aid for Scientific Research (KAKENHI) (17K01974, 19H05015, 21H04786 and 21K06391), Suzuken Memorial Foundation, and the Takeda Science Foundation. KS was supported by JSPS Grants-in-Aid for Scientific Research (KAKENHI) (22K06445), Takeda Science Foundation, and Research Grant for Young Scholars funded by Yamanashi Prefecture. SK was supported by Grants-in-Aid for Scientific Research (KAKENHI) (JP25117003, 18H0512, 19H04746, 20H05060, 20H05902, 21H04786, 21K19309, 23K18162), Japan Agency for Medical Research and Development–Core Research for Evolutional Science and Technology (JP20gm1310008), Core Research for Evolutional Science and Technology (JPMJCR14G2), the Mitsubishi Foundation, the Takeda Science Foundation, and a Frontier Brain Science Grant from the University of Yamanashi.

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