Tuning and fine-tuning of synapses with adenosine

Abstract

The 'omnipresence' of adenosine in all nervous system cells (neurons and glia) together with the intensive release of adenosine following insults, makes adenosine as a sort of 'maestro' of synapses leading to the homeostatic coordination of brain function. Besides direct actions of adenosine on the neurosecretory mechanisms, where adenosine operates to tune neurotransmitter release, receptor-receptor interactions as well as interplays between adenosine receptors and transporters occur as part of the adenosine's attempt to fine tuning synaptic transmission. This review will focus on the different ways adenosine can use to trigger or brake the action of several neurotransmitters and neuromodulators. Adenosine receptors cross talk with other G protein coupled receptors (GPCRs), with ionotropic receptors and with receptor kinases. Most of these interactions occur through A2A receptors, which in spite their low density in some brain areas, such as the hippocampus, may function as metamodulators. Tonic adenosine A2A receptor activity is a required step to allow synaptic actions of neurotrophic factors, namely upon synaptic transmission at both pre- and post-synaptic level as well as upon synaptic plasticity and neuronal survival. The implications of these interactions in normal brain functioning and in neurologic and psychiatric dysfunction will be discussed.

Keywords: Adenosine; G protein coupled receptors; epilepsy; ionotropic receptors; metamodulation; neurodegenerative diseases; receptor cross-talk; receptor kinases..

Fig. (1)

Schematic representation of the reported cross-talk between adenosine receptors and receptors for neuropeptides. The putative therapeutic value of those interactions is also indicated. (+) denotes facilitation and (-) denotes inhibition. See text and references (indicated in brackets) for details.

Fig. (2)

Schematic representation of the reported cross-talk between adenosine receptors and metabotropic glutamate receptors. The coupling of each receptor to G proteins (αβγ subunits) is also indicated. (+) denotes facilitation and (-) denotes inhibition. Whenever the mechanisms involved in the interaction have been evaluated, they are indicated close to the arrow. PKC: protein kinase C. See text and references (indicated in brackets) for details.

Fig. (3)

Schematic representation of the reported cross-talk between adenosine A2A receptors and CB1 receptors and corresponding implications for drug addiction. (+) denotes facilitation and (-) denotes inhibition. Whenever the mechanisms involved in the interaction have been evaluated, they are indicated close to the arrow. cAMP: cyclic AMP; DARPP-32: Dopamine- and cAMPregulated phosphoprotein. See text and references (indicated in brackets) for details.

Fig. (4)

Schematic representation of the reported cross-talk among different purine receptors. Interaction with equilibrative nucleoside transporter (ENT) is also indicated. (+) denotes facilitation and (-) denotes inhibition. Evidence for tight molecular interactions, that may involve heteromerization, is also pointed out. See text and references (indicated in brackets) for details.

Fig. (5)

Negative and positive actions of A1 and A2A adenosine receptors to protect neuronal cells. Note that whereas A1 receptors possess predominant neuroprotective actions, A2A receptors may operate mechanisms leading to neuronal protection or damage. A better knowledge of the time windows for those actions, and how to manipulate them will allow the increase in the therapeutic potential of adenosine related drugs.