Elsevier

Progress in Neurobiology

Volume 83, Issue 5, December 2007, Pages 263-276
Progress in Neurobiology

Aspects of the general biology of adenosine A2A signaling

https://doi.org/10.1016/j.pneurobio.2007.07.005Get rights and content

Abstract

Many of our current hopes of finding better ways to treat Parkinson's disease or to stop its progression rely on studies of adenosine A2A receptors in the brain. Yet any drug targeting central receptors will also potentially affect receptors in other sites. Furthermore, several fundamental aspects of adenosine receptor biology must be taken into account. For these reasons the “Targeting adenosine A2A receptors in Parkinson's disease and other CNS disorders” meeting in Boston included selected aspects of the general biology of adenosine A2A receptor signaling. Some of the presentations from this part of the meeting are summarized in this first chapter. As will be apparent to the reader, these different parts do not form an integrated whole, but they do indicate areas the organizers felt might illuminate remaining questions regarding the roles of adenosine A2A receptors. The contributors to this part of the meeting have summarized some of the key questions below.

Section snippets

Endogenous ligand: level and regulation

Adenosine is the main natural ligand at the four well-conserved adenosine receptors (Fredholm et al., 2001). Inosine also has a weak stimulatory effect at adenosine A1 and A3 receptors (Jin et al., 1997, Fredholm et al., 2001b). Adenosine is not a transmitter substance that is stored in vesicles and released from nerve cells following their activation. Instead it can be released from any cell when the intracellular concentration goes up because of increased intracellular formation of the

A2A receptor: gene structure and transcriptional regulation

The A2A receptor exists in a wide variety of organs including major peripheral tissues (e.g., liver, heart, lung, and the immune system) and the central nervous system (CNS) (Ledent et al., 1997, Lee et al., 2003). In the developing rat brain, expression of the A2A receptor is transiently regulated in various areas (e.g., the striatum, cortex, and hippocampus), perhaps implying a role of adenosine in neuronal development (Weaver, 1993). Soon after neurogenesis, the A2A receptor is highly

Signal transduction

The adenosine A2A receptor couples primarily to members of the Gs family. Like other G protein-coupled receptors (GPCRs) it can also interact with other G proteins if the receptor is very over-expressed, but the evidence for such coupling in vivo is not compelling. In striatum the A2A receptor interacts with Golf proteins (Kull et al., 2000, Corvol et al., 2001). Elsewhere the preferred partner is Gs. It is not known if there are significant differences in receptor affinity or in signaling

Homo- and heterodimers of A2A receptors and possible roles

In the early 1980s Fuxe and Agnati proposed a direct molecular interaction between receptors for neurotransmitters and neuromodulators (Agnati et al., 1980). Approximately 10 years later Ng et al., 1994a, Ng et al., 1994b showed that dopamine receptors occurred as dimers when expressed in insect cells. Also in the mid 1990s the group of Franco found evidence for dimers of A1 receptors in extracts from brain (Ciruela et al., 1995). Since the year 2000, the number of receptors that have been

Immune function of A2A adenosine receptors: interactions between adenosine A2A and A2B receptors and hypoxia-inducible factor 1α

As will become apparent in subsequent chapters (Chen et al.; Morelli et al., this issue), it is increasingly obvious that neuronal A2A signaling cannot explain all aspects of the role of this receptor in Parkinson's disease. Increasing evidence from both animal and human studies suggests that inflammation and immune competent cells play an important role in PD pathogenesis. It is therefore apropos to briefly highlight key aspects of A2A signaling in the regulation of the immune system, even

Summary

Despite the recent advances in our understanding of A2A receptors, much remains to be studied. The eventual development of therapies based on adenosine A2A receptor function will depend to some extent on the answers to remaining questions regarding the fundamental receptor biology of A2A receptors. Some of the key questions are listed below:

  • 1.

    What mechanisms regulate ATP release and which cells are most important? This is vital since ATP released from cells may be an important source of synaptic

Acknowledgements

The original work briefly described was supported in part by grants from Swedish Science Research Council (project no. 2553), by grant SAF2006/05481 from the “Plan Nacional de Investigación” of Spanish Government, grants from the National Science Council (NSC 95-2321-B-001 -023) and the Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan.

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