The regulator of G protein signaling RGS9 supports insulin secretion in male mouse islets
- 1University of Montreal Hospital Research Center (CRCHUM), Montreal, QC, Canada
- 2Department of Medicine, University of Montreal, Montreal, QC, Canada
Abstract
Objectives Regulators of G protein signaling (RGS) proteins terminate G protein-coupled receptor signaling and regulate multiple aspects of pancreatic islet function. Although RGS9 is highly enriched in human and rodent islets, its cellular localization and physiological role remain largely unknown. Here, we investigated the expression of Rgs9 in mouse islets and its contribution to insulin secretion. Methods Rgs9 expression was characterized by RNA in situ hybridization and fluorescence-activated cell sorting coupled with quantitative PCR. Rgs9 function was investigated by shRNA-mediated knockdown in wild-type and Dishevelled, Egl-10 and Pleckstrin (DEP) domain-deficient Rgs9 mutant (Rgs9{Delta}DEP/{Delta}DEP) mouse pseudo-islets. Results Rgs9 was detected throughout the endocrine pancreas but was enriched in {beta} and {delta}cells, with the Rgs9-1 isoform representing the predominant splice variant in mouse islets. Rgs9 knockdown in mouse pseudo-islets impaired glucose- and KCl-stimulated insulin secretion without affecting insulin content. In contrast, Rgs9{Delta}DEP/{Delta}DEP mouse islets failed to reproduce this phenotype. Further characterization of the mutant mice revealed persistent expression of Rgs9 transcripts, which when knocked down impaired both glucose- and KCl-stimulated insulin secretion. Conclusions These data indicate that RGS9 supports glucose-stimulated insulin secretion. Given that RGS9 acts exclusively on Gi/o, our results further suggest that RGS9 in {beta} cells dampens inhibitory signaling to promote insulin secretion. Finally, the Rgs9{Delta}DEP/{Delta}DEP mutant does not represent a complete loss-of-function in islets likely due to the retention of the GTPase-activating protein (GAP) activity in the absence of the DEP domain.
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BibTeX
@misc{reininger2026regulator,
title = {{The regulator of G protein signaling RGS9 supports insulin secretion in male mouse islets}},
author = {Laura Reininger and Sarah Ferragne and Scott A. Campbell and Caroline Tremblay and Mélanie Éthier and Julien Ghislain and Vincent Poitout},
howpublished = {bioRxiv},
year = {2026},
month = oct,
doi = {10.64898/2026.10.26.761401},
url = {https://www.biorxiv.org/content/10.64898/2026.10.26.761401v1},
note = {CC BY-NC-ND},
}
RIS
TY - UNPB
TI - The regulator of G protein signaling RGS9 supports insulin secretion in male mouse islets
AU - Laura Reininger
AU - Sarah Ferragne
AU - Scott A. Campbell
AU - Caroline Tremblay
AU - Mélanie Éthier
AU - Julien Ghislain
AU - Vincent Poitout
PY - 2026
DA - 2026/10/26
PB - bioRxiv
DO - 10.64898/2026.10.26.761401
UR - https://www.biorxiv.org/content/10.64898/2026.10.26.761401v1
AB - Objectives Regulators of G protein signaling (RGS) proteins terminate G protein-coupled receptor signaling and regulate multiple aspects of pancreatic islet function. Although RGS9 is highly enriched in human and rodent islets, its cellular localization and physiological role remain largely unknown. Here, we investigated the expression of Rgs9 in mouse islets and its contribution to insulin secretion. Methods Rgs9 expression was characterized by RNA in situ hybridization and fluorescence-activated cell sorting coupled with quantitative PCR. Rgs9 function was investigated by shRNA-mediated knockdown in wild-type and Dishevelled, Egl-10 and Pleckstrin (DEP) domain-deficient Rgs9 mutant (Rgs9{Delta}DEP/{Delta}DEP) mouse pseudo-islets. Results Rgs9 was detected throughout the endocrine pancreas but was enriched in {beta} and {delta}cells, with the Rgs9-1 isoform representing the predominant splice variant in mouse islets. Rgs9 knockdown in mouse pseudo-islets impaired glucose- and KCl-stimulated insulin secretion without affecting insulin content. In contrast, Rgs9{Delta}DEP/{Delta}DEP mouse islets failed to reproduce this phenotype. Further characterization of the mutant mice revealed persistent expression of Rgs9 transcripts, which when knocked down impaired both glucose- and KCl-stimulated insulin secretion. Conclusions These data indicate that RGS9 supports glucose-stimulated insulin secretion. Given that RGS9 acts exclusively on Gi/o, our results further suggest that RGS9 in {beta} cells dampens inhibitory signaling to promote insulin secretion. Finally, the Rgs9{Delta}DEP/{Delta}DEP mutant does not represent a complete loss-of-function in islets likely due to the retention of the GTPase-activating protein (GAP) activity in the absence of the DEP domain.
SN - 2692-8205
ER -