Abstract
The motor symptoms of Parkinson’s disease (PD) result from striatal dopamine (DA) deficiency due to a progressive degeneration of nigral dopaminergic cells. Although DA replacement therapy is the mainstay to treat parkinsonian symptoms, a long-term daily administration of levodopa often develops levodopa-induced dyskinesia (LID). LID is closely linked to the dysregulation of cyclic adenosine monophosphate (cAMP) signaling cascades in the medium spiny neurons (MSNs), the principal neurons of the striatum, which are roughly halved with striatonigral MSNs by striatopallidal MSNs. The olfactory type G-protein α subunit (Gαolf) represents an important regulator of the cAMP signal activities in the striatum, where it positively couples with D1-type dopamine receptor (D1R) and adenosine A2A receptor (A2AR) to increase cAMP production in the MSNs. Notably, D1Rs are primarily expressed in striatonigral MSNs, whereas D2Rs and A2ARs are expressed in striatopallidal MSNs. Based on the evidence obtained from parkinsonian mice, we hypothesized that in the DA-denervated striatum with D1R hypersensitivity, a repeated and pulsatile exposure to levodopa might cause a usage-induced degradation of Gαolf proteins in striatal MSNs, resulting in increased and decreased levels of Gαolf protein in the striatonigral and striatopallidal MSNs, respectively. As a principal cause for generating LID, this might lead to an increased responsiveness to levodopa exposure in both striatonigral and striatopallidal MSNs. Our hypothesis reinforces the long-standing concept that LID might result from the reduced activity of the striatopallidal pathway and has important clinical implications.
Highlights
By transducing extracellular signals carried by neuromodulators, the cyclic adenosine monophosphate signaling plays a crucial role in the regulation of neuronal activities in the brain
Since the intracellular cyclic adenosine monophosphate (cAMP) signaling cascades serve as a determinant of striatal cell activities (Girault, 2012), maladaptive change in Gαolf protein levels is thought to be closely linked to the pathophysiology of Parkinson’s disease (PD) (Hervé, 2011)
We hypothesized that DA depletion might cause a marked upregulation of the Gαolf protein levels in striatonigral medium spiny neurons (MSNs), which results in a crucial hypersensitivity of the striatum to D1-type receptors (D1Rs) stimulation in PD
Summary
By transducing extracellular signals carried by neuromodulators, the cyclic adenosine monophosphate (cAMP) signaling plays a crucial role in the regulation of neuronal activities in the brain. It has been suggested that LID is associated with the hypersensitivity of striatal MSNs to DA receptor stimulation and with ongoing deregulation of corticostriatal inputs, which activate striatal glutamate receptors, such as N-methyl-D-aspartate (NMDA) receptors (Brotchie, 2005; Jenner, 2008; Bastide et al, 2015; Calabresi et al, 2016) In this hypothesis article, we primarily considered the levodopa-induced changes in cellular Gαolf protein levels in the DA-denervated striatum as the key mechanism to increase the striatal responsiveness to DA receptor stimulation in LID. The Gαolf protein level plays a key role in regulating the D1R/cAMP- and A2AR/cAMP-signal activities of striatonigral and striatopallidal MSNs, respectively. As D2R activation inhibits AC5 through Gi/o proteins but A2AR activation elicits AC5 through Gs/olf proteins (Kull et al, 2000), the A2AR/Gαolf-signal stimulation functionally opposes the actions of D2Rs on the striatopallidal MSNs (Schwarzschild et al, 2006; Fuxe et al, 2007)
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