Abstract
Parkinson’s disease (PD) is a neurodegenerative disorder characterized by motor control deficits, which is associated with the loss of striatal dopaminergic neurons from the substantia nigra. In parallel to dopaminergic denervation, there is an increase of acetylcholine within the striatum, resulting in a striatal dopaminergic–cholinergic neurotransmission imbalance. Currently, available PD pharmacotherapy (e.g., prodopaminergic drugs) does not reinstate the altered dopaminergic–cholinergic balance. In addition, it can eventually elicit cholinergic-related adverse effects. Here, we investigated the interplay between dopaminergic and cholinergic systems by assessing the physical and functional interaction of dopamine D2 and muscarinic acetylcholine M1 receptors (D2R and M1R, respectively), both expressed at striatopallidal medium spiny neurons. First, we provided evidence for the existence of D2R–M1R complexes via biochemical (i.e., co-immunoprecipitation) and biophysical (i.e., BRET1 and NanoBiT®) assays, performed in transiently transfected HEK293T cells. Subsequently, a D2R–M1R co-distribution in the mouse striatum was observed through double-immunofluorescence staining and AlphaLISA® immunoassay. Finally, we evaluated the functional interplay between both receptors via behavioral studies, by implementing the classical acute reserpine pharmacological animal model of experimental parkinsonism. Reserpinized mice were administered with a D2R-selective agonist (sumanirole) and/or an M1R-selective antagonist (VU0255035), and alterations in PD-related behavioral tasks (i.e., locomotor activity) were evaluated. Importantly, VU0255035 (10 mg/kg) potentiated the antiparkinsonian-like effects (i.e., increased locomotor activity and decreased catalepsy) of an ineffective sumanirole dose (3 mg/kg). Altogether, our data suggest the existence of putative striatal D2R/M1R heteromers, which might be a relevant target to manage PD motor impairments with fewer adverse effects.
Highlights
Parkinson’s disease (PD) is a common movement disorder that is clinically characterized by motor control deficits, such as bradykinesia, muscular rigidity, resting tremors, and postural instability (Mhyre et al, 2012)
When HAM1R was immunoprecipitated from FLAG-D2R and HA-M1R co-transfected Human embryonic kidney 293T (HEK293T) cells, a specific immunoreactive band of 90 to 100 kDa corresponding to FLAG-D2R was detected (Figure 1A, IPs)
These results indicate that D2R and M1R are expressed within the same membrane context and are prone to interact
Summary
Parkinson’s disease (PD) is a common movement disorder that is clinically characterized by motor control deficits, such as bradykinesia, muscular rigidity, resting tremors, and postural instability (Mhyre et al, 2012). DA receptor agonists (i.e., pramipexole and ropinirole) are considered the first choice in PD therapy, as monotherapy or adjuvants to L-DOPA (Fox et al, 2011; Fox et al, 2018) These agonists are effective at the early stages, but they eventually fail reducing motor complications (Jenner, 2003; Hisahara and Shimohama, 2011). Anticholinergics (i.e., biperiden) are eventually used as adjuvant drugs in PD management, besides their adverse effects (i.e., nausea, cognitive impairments, dry mouth, urinary retention, and blurred vision) Some of these adverse effects are likely due to a lack of muscarinic acetylcholine receptor (mAChR) subtype selectivity, because both M2R and M3R are blocked (Chen and Swope, 2007; Pedrosa and Timmermann, 2013). Cholinergic modulation of striatal functions has gained renewed interest because of the development of compounds targeting specific mAChR subtypes (Xiang et al, 2012; Shen et al, 2015; Ztaou et al, 2016; Lv et al, 2017; Chambers et al, 2019)
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