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Institute of Pharmacology, Center of Biomolecular Medicine and Pharmacology, Medical University of Vienna, Vienna, Austria
Received May 17, 2006; accepted May 17, 2006
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Abstract |
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 Top Abstract Adenosine and NeuroprotectionPC-12 Cell Differentiation As...An Alternative Signaling Pathway...The A2A Receptor C...References |
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-arrestin family. These -arrestins bind to residues that have been phosphorylated by specialized kinases (G protein-coupled receptor kinases) and thereby initiate receptor desensitization and endocytosis. More recently, it has become clear that many additional "accessory" proteins bind to C termini of G protein-coupled receptors. The article by Sun et al. (p. 454) in the current issue of Molecular Pharmacology identifies translin-associated protein-X as yet another interaction partner of the A2A receptor; translin-associated protein allows the A2A receptor to impinge on the signaling mechanisms by which p53 regulates neuronal differentiation, but the underlying signaling pathways are uncharted territory. With a list of five known interaction partners, the C terminus of the A2A receptor becomes a crowded place. Hence, there must be rules that regulate the interaction. This allows the C terminus to act as coincidence detector and as signal integrator. Despite our ignorance about the precise mechanisms, the article has exciting implications: the gene encoding for translin-associated protein-X maps to a locus implicated in some forms of schizophrenia; A2A receptor agonists are candidate drugs for the treatment of schizophrenic symptoms. It is of obvious interest to explore a possible link.
). The widespread expression of adenosine receptors is also consistent with its role in mediating cellular protection: there are no tissues or organs that are not responsive to adenosine. The retaliatory action of adenosine results from the concerted stimulation of four adenosine receptors, termed A1-, A2A-, A2B-, and A3-adenosine receptors. These receptors differ in their affinity for adenosine, in the type of G proteins that they engage, and, hence, in the downstream signaling pathways that are activated in the receptive cells (Klinger et al., 2002a). |
Adenosine and Neuroprotection |
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TopAbstractAdenosine and NeuroprotectionPC-12 Cell Differentiation As...An Alternative Signaling Pathway...The A2A Receptor C...References |
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). Thus, ATP, ADP, and adenosine participate in neurotransmission; the activation status of neurons is believed to specify the relative contribution of individual receptors in this purinergic network (Moskvina et al., 2003). Most of us are familiar with the immediate central nervous system depression that results from the accumulation of extracellular adenosine: we choose to antagonize it on a more or less regular basis by the intake of various caffeine-containing beverages. Everyday experience thus renders accessible the immediate effects that adenosine exerts on the brain via G protein-dependent signaling pathways. It is much less clear how adenosine receptors can also interfere with long-term decisions in the brain (i.e., proliferation, differentiation and outgrowth of neurite extensions that will give rise to axons and dendrites). Several observations have kindled interest in this area:
). It should be noted that this model has been questioned (Stein et al., 2001). ). This observation is surprising, because the A1 receptor mediates depression of neuronal activity via Gi/Go-induced K+-channel activation and inhibition of neuronal Ca2+ channels, and this is likely to alleviate excitotoxicity (kainate acts via ionotropic glutamate receptor). In contrast, it is intuitively less evident how the Gs-coupled A2A receptor allows neurons to survive ). Transactivation refers to the fact that tyrosine kinase receptors can be recovered in active (i.e., phosphorylated) form from cellular lysates, although the cells have not been stimulated by their cognate ligand(s) but rather by a G protein-coupled receptor. The A2A receptor triggers transactivation of TrkA and TrkB in PC-12 cells and hippocampal neurons, respectively (Lee and Chao, 2001). The precise mechanism is not clear, but transactivation requires the nonreceptor tyrosine kinase src, which also plays a prominent role in A2A receptor mediated activation of mitogen-activated protein (MAP) kinase in several cell types, including PC-12 cells (Klinger et al., 2002b). |
PC-12 Cell Differentiation As a Model System |
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TopAbstractAdenosine and NeuroprotectionPC-12 Cell Differentiation As...An Alternative Signaling Pathway...The A2A Receptor C...References |
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). In this model, epidermal growth factor (EGF) failed to induce differentiation, because it only caused a transient increase in MAP kinase activity (Traverse et al., 1992). The deficiency of EGF is remedied if the receptor is overexpressed (Traverse et al., 1994). It has long been known that A2A receptor stimulation may cause growth arrest in PC-12 cells (Huffaker et al., 1984) and synergize with NGF in the induction of differentiation markers (Guroff et al., 1981). It is noteworthy that these earlier observations indicated that stimulation of cAMP was not required, because the adenosine-induced growth arrest was not abolished by 3',5'-dideoxyadenosine, a direct ("P-site") inhibitor of adenylyl cyclase (Huffaker et al., 1984). However, it is still possible to reconcile these findings with the above model, in which sustained activation of MAP kinase is the crucial signal for differentiation: the A2A receptor can stimulate MAP kinase in both a Gs-dependent and -independent manner (Sexl et al., 1997; Seidel et al., 1999). |
An Alternative Signaling Pathway and Its Implications |
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TopAbstractAdenosine and NeuroprotectionPC-12 Cell Differentiation As...An Alternative Signaling Pathway...The A2A Receptor C...References |
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) propose an alternative pathway: the A2A receptor generates two signals, one that relies on cAMP and protein kinase A-dependent phosphorylation of cAMP response element-binding protein (Cheng et al., 2002) and a second one that relies on a hitherto-unappreciated interaction partner, translin-associated protein-X (TRAX). In the absence of functional p53, differentiation of PC-12 cells is abrogated and activation of p53 is downstream of NGF-induced activation of p21ras; p53-dependent induction of the cyclin-dependent kinase inhibitor p21cip1 is likely to account for the NGF-induced cell cycle arrest (Hughes et al., 2000). Sun et al. (2006) show that stimulation of the A2A receptor can bypass the requirement of p53 provided that TRAX is present.
It is not clear how TRAX works. In fact, its biochemical activities are poorly understood; TRAX can form complexes with translin (the mouse ortholog of which is referred to as TB-RBP, testis-brain RNA-binding protein). This may interfere with the ability of translin to bind (dendritic) mRNA (Chennathukuzhi et al., 2001). In view of our ignorance, why is the interaction between translin-associated protein-X and the A2A receptor exciting news? The gene encoding translin-associated protein-X maps to a region on chromosome 1 (1q42
[PDB]
) that is disrupted in some instances of schizophrenia (Millar et al., 2000); some haplotypes of the TRAX gene are in fact associated with the disease (Cannon et al., 2005). On the other hand, in rodents, A2A receptor agonists elicit effects that are predictive of an antipsychotic action (i.e., a therapeutic efficacy in schizophrenia) (Kafka and Corbett, 1996; Rimondini et al., 1997). Thus, it is tantalizing to suspect that this may be more than a fortuitous coincidence.
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The A2A Receptor C Terminus—A Crowded Place |
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TopAbstractAdenosine and NeuroprotectionPC-12 Cell Differentiation As...An Alternative Signaling Pathway...The A2A Receptor C...References |
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) and for G protein coupling (Klinger et al., 2002c). G protein-coupled receptors bind proteins other than G proteins, G protein-coupled receptor kinases, and -arrestins (which support the eponymous signaling processes and initiate receptor desensitization). The list of these accessory proteins is rapidly growing (Bockaert et al., 2004). Table 1 gives an overview over accessory proteins that have been found to bind to the A2A receptor. Although the length of the C terminus (
120 amino acids) may provide a lot of binding sites, the size of the individual binding partners [e.g., ADP-ribosylation factor nucleotide site opener (ARNO), 47 kDa; TRAX, 33 kDa] makes it unlikely that there is enough space for the simultaneous binding of all interaction partners. It is substantially more probable that any given interactor binds transiently and in a regulated manner. This may allow the C terminus to serve as a coincidence detector (the binding of agonist and a second signal must occur simultaneously for interactor recruitment/release) or as a signal integrator (several inputs must accumulate sequentially before interactor recruitment/release). Finally, the presence of absence of these accessory proteins may explain conflicting results. As mentioned above, A2A agonists afford neuroprotection; this effect has been exploited for devising therapeutic strategies in spinal cord injury (Okonkwo et al., 2006). However, there is also evidence that A2A antagonists—rather than agonists—are neuroprotective. In humans, consumption of caffeine protects against the development of Parkinson's disease; this effect has been confirmed in large prospective cohort studies and has been linked to blockage of A2A receptors in the striatum (Ross et al., 2000; Ascherio et al., 2001). Neuroprotection by A2A-antagonists can also be recapitulated in experimental models of toxin-induced degeneration of dopaminergic nigrostriatal projections (Pierri et al., 2005). It is therefore conceivable that the outcome of adenosine receptor stimulation (neuroprotection versus neurotoxicity) is contingent on the interaction partners of the receptors.
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Footnotes |
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ABBREVIATIONS: MAP, mitogen-activated protein; NGF, nerve growth factor; EGF, epidermal growth factor, TRAX, translin-associated protein-X.
Address correspondence to: Michael Freissmuth, Institute of Pharmacology, Medical University of Vienna, Währinger Str. 13a, A-1090 Vienna, Austria. E-mail: michael.freissmuth{at}meduniwien.ac.at
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References |
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TopAbstractAdenosine and NeuroprotectionPC-12 Cell Differentiation As...An Alternative Signaling Pathway...The A2A Receptor C...References |
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