Adenosine and its receptors

Adenosine is a ubiquitous chemical messenger that modulates cellular activity in both the CNS and peripheral organs.^1–5 Adenosine levels in the brain extracellular space increase dramatically during metabolically stressful conditions, such as ischemia, seizures, or trauma. Adenosine, acting via different receptors, modulates excitability in the CNS^2–4 and has a role in mechanisms of seizure susceptibility,^5,6 sleep induction,⁷ basal ganglia function,⁸ pain perception,⁹ cerebral blood flow,¹⁰ and respiration.¹¹ Adenosine receptors are inhibited by caffeine and other methylxanthines and provide a potential target for treatment of cerebral ischemia,¹² seizures,¹³ pain,⁹ Parkinson disease (PD),^8,14 and Huntington disease.¹⁵ There are several excellent reviews on recent experimental findings and insights into adenosine signaling in the CNS,^1–6,8 and on adenosine as a potential therapeutic target in neurologic disorders.^{5–7,12–15}

ADENOSINE SIGNALING IN THE NERVOUS SYSTEM

There is tight and dynamic regulation of adenosine levels in the nervous system.^1–5 All cell types contribute to the accumulation of extracellular adenosine (figure). Extracellular concentrations of adenosine are determined by the interplay between the activity of intracellular and extracellular enzymes involved in adenosine metabolism and the transport of adenosine across the cell membrane. Metabolic stress triggers the dephosphorylation of adenosine triphosphate (ATP) and formation of adenosine monophosphate (AMP), which is converted to adenosine by 5′-nucleotidase. Adenosine is then released from cells by facilitated diffusion via nucleoside transporters, the best characterized being the equilibrative nucleoside transporters (ENT).¹⁶ Adenosine may also be produced by the extracellular metabolism of ATP via a cascade of ectonucleases.^2–4 The primary route of adenosine metabolism is adenosine kinase (ADK), which is expressed primarily in astrocytes (figure). The concentration of extracellular adenosine increases dramatically in the setting of metabolic stress such as hypoxia, ischemia, trauma, or seizures.^2–5,12 Transport from the astrocyte is the primary source of …