Abstract
The adenosine homo, iso and heteroreceptor complexes in the basal ganglia play a highly significant role in modulating the indirect and direct pathways and the striosomal projections to the nigro-striatal DA system. The major adenosine receptor complexes in the striato-pallidal GABA neurons can be the A2AR–D2R and A2AR–D2R–mGluR5 receptor complexes, in which A2AR protomers and mGluR5 protomers can allosterically interact to inhibit D2R protomer signaling. Through a reorganization of these heteroreceptor complexes upon chronic dopaminergic treatment a pathological and prolonged inhibition of D2R receptor protomer signaling can develop with motor inhibition and wearing off of the therapeutic effects of levodopa and dopamine receptor agonists. The direct pathway is enriched in D1R in and around glutamate synapses enhancing the ability of these GABA neurons to be activated and increase motor initiation. The brake on these GABA neurons is in this case exerted by A1R forming A1R–D1R heteroreceptor complexes in which they allosterically inhibit D1R signaling and thereby reduce motor initiation. Upon chronic levodopa treatment a reorganization of the D1R heteroreceptor complexes develops with the formation of putative A1R–D1R–D3 in addition to D1R–D3R complexes in which D3R enhances D1R protomer signaling and may make the A1R protomer brake less effective. Alpha-synuclein monomers–dimers are postulated to form complexes with A2AR homo and heteroprotomers in the plasma membrane enhancing alpha-synuclein aggregation and toxicity. The alpha-synuclein fibrils formed in the A2AR enriched dendritic spines of the striato-pallidal GABA neurons may reach the surrounding DA terminals via extracellular-vesicle-mediated volume transmission involving internalization of the vesicles and their cargo (alpha-synuclein fibrils) into the vulnerable DA terminals, enhancing their degeneration followed by retrograde flow of these fibrils in the DA axons to the vulnerable nigral DA nerve cells.
Highlights
There exists substantial evidence for the existence of G protein-coupled receptor (GPCR) homo and heteroreceptor complexes with allosteric receptor–receptor interactions in
Homo and heteroreceptor receptor complexes with allosteric receptor–receptor interactions give a new dimension to molecular neuroscience and brain integration and represents a new biological principle to integrate biological signals in all tissues
The signaling consequences of the association of two or several receptors leading to the formation of heteroreceptor complexes can be marked, dynamic and take place via the allosteric receptor–receptor interactions including the receptor–protein interactions, especially the adaptor proteins (Fig. 1)
Summary
Adenosine is a significant neuromodulator in the CNS that originates from the ATP located intracellularly and extracellularly in the neuronal and glial cells. Adenosine is generated from ATP which upon exocytosis from neurons and glial cells is rapidly converted to adenosine by 5′ectonucleotidases, which are in abundance in striatum It uses volume transmission for communication taking place in the extracellular space of the brain through diffusion and flow (Fuxe et al 2010a). The A2AR enhances the activity of these neurons mainly through allosteric inhibition of the Gi/o mediated D2R protomer signaling in an A2AR–D2R heteroreceptor complex located in the soma-dendritic level of these GABA neurons (Fuxe et al 2007b, 2010b). We will give an update on the existence and function of adenosine isoreceptor and heteroreceptor complexes in the brain both in terms of transmission and of neurodegeneration
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