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Abstract
Adenosine is a nucleoside mainly formed by degradation of ATP, located intracellularly or extracellularly, and acts as a neuromodulator. It operates as a volume transmission signal through diffusion and flow in the extracellular space to modulate the activity of both glial cells and neurons. The effects of adenosine are mediated via four adenosine receptor subtypes: A1R, A2AR, A2BR, A3R. The A2AR has a wide-spread distribution but it is especially enriched in the ventral and dorsal striatum where it is mainly located in the striato-pallidal GABA neurons at a synaptic and extrasynaptic location. A number of A2AR heteroreceptor complexes exist in the striatum. The existence of A2AR-D2R heteroreceptor complexes with antagonistic A2AR-D2R interactions in the striato-pallidal GABA neurons is well-known with A2AR activation inhibiting Gi/o mediated signaling of D2Rs. A2AR-mGluR5 heteroreceptor complexes were also found in with synergistic receptor-receptor interactions enhancing the inhibition of the D2R protomer signaling. They are located mainly in extrasynaptic regions of the striato-pallidal GABA neurons. Results recently demonstrated the existence of brain A2AR-A2BR heteroreceptor complexes, in which A2BR protomer constitutively inhibited the function of the A2AR protomer. These adenosine A2AR heteroreceptor complexes may modulate alpha-synuclein aggregation and toxicity through postulated bidirectional direct interactions leading to marked increases in A2AR signaling both in nerve cells and microglia. It is of high interest that formation of A2AR-A2ABR heteroreceptor complexes provides a brake on A2AR recognition and signaling opening up a novel strategy for treatment of A2AR mediated neurodegeneration.
Highlights
Adenosine is a nucleoside mainly formed by degradation of ATP located intracellularly or extracellularly and acts as a neuromodulator (Fredholm, 1995; Gomes et al, 2011)
The exciting work performed on A2AR mediated neurodegeneration performed by several groups (Gomes et al, 2011; Santiago et al, 2014; Laurent et al, 2016; Ferreira et al, 2017a) opens up a major role for A2AR antagonists in neurodegenerative disease involving alpha-synucleins
In this perspective article we have proposed that adenosine A2AR iso- and heteroreceptor complexes and their allosteric receptor-receptor interactions can be key players in balance with corresponding homorecepor complexes
Summary
Adenosine is a nucleoside mainly formed by degradation of ATP located intracellularly or extracellularly and acts as a neuromodulator (Fredholm, 1995; Gomes et al, 2011). It seems possible that the increased A2AR activation can bring down the activity of alpha-synuclein induced clearance via autophagy involving reduced lysosomal function (Decressac et al, 2013) Such events blocked by A2AR antagonists may FIGURE 1 | Illustration of the adenosine heteroreceptor complexes found in the GPCR heteroreceptor network (GPCR-hetnet; left large panel) and the synaptic and extrasynaptic regions of the glutamate synapse in the striato-pallidal GABA neurons (right panel). Putative A2AR-D2R-NMDAR Heteroreceptor Complexes The existence of A2AR-D2R heteroreceptor complexes with antagonistic A2AR-D2R interactions is well-known with A2AR activation inhibiting Gi/o mediated signaling of D2Rs (Hillion et al, 2002; Canals et al, 2003; Navarro et al, 2009, 2010; Borroto-Escuela et al, 2010a,b, 2013b; Figures 1, 2) They are highly expressed in the striato-pallidal GABA neurons in synaptic and extrasynaptic location related to glutamate synapses (Fuxe et al, 2005, 2010, 2014c,d). The function of complexes including A3R has not yet been clarified
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