Adenosine signaling and function in glial cells

Abstract

Despite major advances in a variety of neuroscientific research fields, the majority of neurodegenerative and neurological diseases are poorly controlled by currently available drugs, which are largely based on a neurocentric drug design. Research from the past 5 years has established a central role of glia to determine how neurons function and, consequently, glial dysfunction is implicated in almost every neurodegenerative and neurological disease. Glial cells are key regulators of the brain's endogenous neuroprotectant and anticonvulsant adenosine. This review will summarize how glial cells contribute to adenosine homeostasis and how glial adenosine receptors affect glial function. We will then move on to discuss how glial cells interact with neurons and the vasculature, and outline new methods to study glial function. We will discuss how glial control of adenosine function affects neuronal cell death, and its implications for epilepsy, traumatic brain injury, ischemia, and Parkinson's disease. Eventually, glial adenosine-modulating drug targets might be an attractive alternative for the treatment of neurodegenerative diseases. There are, however, several major open questions that remain to be tackled.

Figure 1

Extracellular adenosine levels are thought to be regulated by an astrocyte-based adenosine-cycle. Astrocytes can release ATP via vesicular release and/or by direct release through hemichannels (h-ch). Extracellular ATP is rapidly degraded into adenosine (ADO) by a series of ectonucleotidases. Adenosine can also be released directly via equilibrative nucleoside transporters (nt). Intracellularly adenosine levels are largely controlled by adenosine kinase, which is part of a substrate cycle between adenosine and AMP. Small changes in adenosine kinase activity rapidly translate into major changes in adenosine. Intracellular adenosine kinase is considered to be a metabolic reuptake system for adenosine. Only selected mechanisms and pathways are shown; for details please refer to main text.

Figure 2

Adenosine receptors, their coupling to G-proteins and some of the down-stream consequences of receptor activation.

Figure 3

Role of the adenosine (ADO) / adenosine kinase (ADK) system in regulating acute and chronic responses to injury. Left: Within hours after brain injury (e.g. stroke, trauma, prolonged seizures) a surge in micromolar levels of ADO results that protects the brain from further injury and from seizures. Hypoxia and trauma can directly lead to a rise in extracellular ATP that is rapidly degraded into adenosine. High levels of adenosine are known to inhibit ADK, further amplifying the adenosine surge. Right: The acute adenosine surge contributes to trigger astrogliosis via a variety of mechanisms that include modulation of astrocytic adenosine receptors (ARs), modulation of inflammatory processes and the release of cytokines. Astrogliosis leads to overexpression of ADK resulting in adenosine-deficiency, which contributes to seizure generation.

Figure 4

The dual functions of A_2A receptor antagonists in Parkinson’s disease models: A_2AR antagonists act at the A_2AR in striatal neurons to stimulate motor activity. Furthermore, it is postulated that A_2AR antagonists may modulate microglial activation in substantia nigra to exert a possible neuroprotective effect in an animal model of Parkinson’s disease.