Aspects of the general biology of adenosine A2A signaling
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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