scholarly journals Modulation of Increased mGluR1 Signaling by RGS8 Protects Purkinje Cells From Dendritic Reduction and Could Be a Common Mechanism in Diverse Forms of Spinocerebellar Ataxia

2021 ◽  
Vol 8 ◽  
Author(s):  
Qin-Wei Wu ◽  
Josef P. Kapfhammer
Keyword(s):  
Purkinje Cells ◽  
Spinocerebellar Ataxia ◽  
Common Mechanism ◽  
G Protein Signaling ◽  
Protein Signaling ◽  
Spinocerebellar Ataxias ◽  
Negative Effects ◽  
The Moment ◽  
Cerebellar Purkinje Cells

Spinocerebellar ataxias (SCAs) are a group of hereditary neurodegenerative diseases which are caused by diverse genetic mutations in a variety of different genes. We have identified RGS8, a regulator of G-protein signaling, as one of the genes which are dysregulated in different mouse models of SCA (e.g., SCA1, SCA2, SCA7, and SCA14). In the moment, little is known about the role of RGS8 for pathogenesis of spinocerebellar ataxia. We have studied the expression of RGS8 in the cerebellum in more detail and show that it is specifically expressed in mouse cerebellar Purkinje cells. In a mouse model of SCA14 with increased PKCγ activity, RGS8 expression was also increased. RGS8 overexpression could partially counteract the negative effects of DHPG-induced mGluR1 signaling for the expansion of Purkinje cell dendrites. Our results suggest that the increased expression of RGS8 is an important mediator of mGluR1 pathway dysregulation in Purkinje cells. These findings provide new insights in the role of RGS8 and mGluR1 signaling in Purkinje cells and for the pathology of SCAs.

scholarly journals Mice With Monoallelic GNAO1 Loss Exhibit Reduced Inhibitory Synaptic Input To Cerebellar Purkinje Cells

2021 ◽  
Author(s):  
Huijie Feng ◽  
Yukun Yuan ◽  
Michael R Williams ◽  
Alex Roy ◽  
Jeffrey Leipprandt ◽  
...  
Keyword(s):  
Synaptic Transmission ◽  
Purkinje Cells ◽  
Gabab Receptor ◽  
Molecular Layer ◽  
Loss Of Function ◽  
Whole Cell Patch Clamp ◽  
The Difference ◽  
G Protein Alpha Subunit ◽  
Cerebellar Purkinje Cells

GNAO1 encodes Gαo, a heterotrimeric G protein alpha subunit in the Gi/o family. In this report, we used a Gnao1 mouse model G203R previously described as a gain-of-function Gnao1 mutant with movement abnormalities and enhanced seizure susceptibility. Here, we report an unexpected second mutation resulting in a loss-of-function Gαo protein and describe alterations in central synaptic transmission. Whole cell patch clamp recordings from Purkinje cells (PCs) in acute cerebellar slices from Gnao1 mutant mice showed significantly lower frequencies of spontaneous and miniature inhibitory postsynaptic currents (sIPSCs and mIPSCs) compared to WT mice. There was no significant change in sEPSCs or mEPSCs. Whereas mIPSC frequency was reduced, mIPSC amplitudes were not affected, suggesting a presynaptic mechanism of action. A modest decrease in the number of molecular layer interneurons was insufficient to explain the magnitude of IPSC suppression. Paradoxically, Gi/o inhibitors (pertussis toxin), enhanced the mutant-suppressed mIPSC frequency and eliminated the difference between WT and Gnao1 mice. While GABAB receptor regulates mIPSCs, neither agonists nor antagonists of this receptor altered function in the mutant mouse PCs. This study is the first electrophysiological investigation of the role of Gi/o protein in cerebellar synaptic transmission using an animal model with a loss-of-function Gi/o protein.

scholarly journals The role of regulator of G protein signaling 4 in delta-opioid receptor-mediated behaviors

2016 ◽  
Vol 234 (1) ◽  
pp. 29-39 ◽  
Author(s):  
Isaac J. Dripps ◽  
Qin Wang ◽  
Richard R. Neubig ◽  
Kenner C. Rice ◽  
John R. Traynor ◽  
...  
Keyword(s):  
G Protein ◽  
Opioid Receptor ◽  
Delta Opioid Receptor ◽  
G Protein Signaling ◽  
Protein Signaling

Toward understanding the role of G-protein signaling

2021 ◽  
Vol 16 ◽  
pp. 51-55
Author(s):  
Ryoji Kise ◽  
Yuki Ono ◽  
Kouki Kawakami ◽  
Asuka Inoue
Keyword(s):  
G Protein ◽  
G Protein Signaling ◽  
Protein Signaling

Modulatory role of serotonin on GABA-elicited inhibition of cerebellar Purkinje cells

Neuroscience ◽  
1989 ◽  
Vol 30 (1) ◽  
pp. 117-125 ◽  
Author(s):  
J.C. Strahlendorf ◽  
M. Lee ◽  
H.K. Strahlendorf
Keyword(s):  
Purkinje Cells ◽  
Cerebellar Purkinje Cells

scholarly journals Distribution of Activator of G-Protein Signaling 3 within the Aggresomal Pathway: Role of Specific Residues in the Tetratricopeptide Repeat Domain and Differential Regulation by the AGS3 Binding Partners Giα and Mammalian Inscuteable

2010 ◽  
Vol 30 (6) ◽  
pp. 1528-1540 ◽  
Author(s):  
Ali Vural ◽  
Sadik Oner ◽  
Ningfei An ◽  
Violaine Simon ◽  
Dzwokai Ma ◽  
...  
Keyword(s):  
G Protein ◽  
G Protein Signaling ◽  
Protein Signaling ◽  
Single Nucleotide ◽  
Signaling Systems ◽  
Binding Partners ◽  
Repeat Domain ◽  
Tetratricopeptide Repeat Domain ◽  
Tpr Domain

ABSTRACT AGS3, a receptor-independent activator of G-protein signaling, is involved in unexpected functional diversity for G-protein signaling systems. AGS3 has seven tetratricopeptide (TPR) motifs upstream of four G-protein regulatory (GPR) motifs that serve as docking sites for Giα-GDP. The positioning of AGS3 within the cell and the intramolecular dynamics between different domains of the proteins are likely key determinants of their ability to influence G-protein signaling. We report that AGS3 enters into the aggresome pathway and that distribution of the protein is regulated by the AGS3 binding partners Giα and mammalian Inscuteable (mInsc). Giα rescues AGS3 from the aggresome, whereas mInsc augments the aggresome-like distribution of AGS3. The distribution of AGS3 to the aggresome is dependent upon the TPR domain, and it is accelerated by disruption of the TPR organizational structure or introduction of a nonsynonymous single-nucleotide polymorphism. These data present AGS3, G-proteins, and mInsc as candidate proteins involved in regulating cellular stress associated with protein-processing pathologies.

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