Adenosine heteroreceptor complexes in the basal ganglia are implicated in Parkinson’s disease and its treatment

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.

Oligomeric Receptor Complexes and Their Allosteric Receptor-Receptor Interactions in the Plasma Membrane Represent a New Biological Principle for Integration of Signals in the CNS

“…The A2AR heteromers can be listed as follows: A1R-A2AR, A2AR-A2BR, A2AR-D2R, A2AR-D3R, A2AR-D4R4. They are usually named A2AR homo, iso, and heteroreceptor complexes in view of the participation of adaptor/chaperone proteins directly binding to the GPCR protomers (Borroto-Escuela and Fuxe, 2019). The A2AR-D2R heteroreceptor complex is of high interest in view of its relevance for Parkinson’s disease, Schizophrenia and cocaine addiction (Fuxe et al, 2014d, 2015; George et al, 2014; Borroto-Escuela et al, 2018d).…”

“…Thus, the A2AR orthosteric binding pocket may be altered through the reorganization. The reorganization may also involve an increased recruitment of mGluR5 to the A2AR-D2R complex which leads to an enhancement of the allosteric inhibition of the D2R protomer signaling in the A2AR-D2R-mGluR5 complex (Fuxe et al, 2003; Antonelli et al, 2006; Borroto-Escuela and Fuxe, 2019). Based on such a view, it may be important to provide the A2AR antagonist early in the treatment of Parkinson’s disease before reorganization of the A2AR-D2R complex.…”

“…Based on such a view, it may be important to provide the A2AR antagonist early in the treatment of Parkinson’s disease before reorganization of the A2AR-D2R complex. This may also reduce the affinity of the A2AR and D2R for each other and instead the formation of D2R homomers and monomers can be favored with improvement of treatment (Borroto-Escuela and Fuxe, 2019).…”

Potentiation of cannabinoid signaling in microglia by adenosine A2A receptor antagonists

“…It has been recently proposed that A 2A R antagonists could also act on neurons to counteract neurodegeneration in Parkinson's disease by interfering with potentiation by agonists of fibrillar alpha‐synuclein accumulation in A 2A R‐rich dorsal striato‐pallidal GABA neurons. The fibrillar alpha‐synuclein may then reach the surrounding vulnerable dopaminergic terminals via extracellular vesicle mediated volume transmission (Borroto‐Escuela & Fuxe, ).…”

Adenosine-Related Mechanisms in Non-Adenosine Receptor Drugs

“…For example, disruption of the A 2A AR-D 2 R complex by an A 2A AR agonist blocks the inhibition of cocaine self-administration [113]. Thus, there can potentially be MoA interactions between ARs and any of the numerous other GPCRs with which they heterodimerize or oligomerize (reviewed in Vecchio et al [114,115]). Interactions of A 2A AR-mGlu 5 R (metabotropic glutamate receptor) are thought to be important in Parkinson's disease.…”