Spinophilin Limits Metabotropic Glutamate Receptor 5 Scaffolding to the Postsynaptic Density and Cell Type Specifically Mediates Excessive Grooming

Morris, Cameron W.; Watkins, Darryl S.; Shah, Nikhil R.; Pennington, Taylor; Hens, Basant; Qi, Guihong; Doud, Emma H.; Mosley, Amber L.; Atwood, Brady K.; Baucum, Anthony J.

doi:10.1016/j.biopsych.2022.12.008

Cited by 4 publications

(3 citation statements)

References 112 publications

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“…This would also contrasts with whole-body spinophilin KO mice which have less circulating insulin (14, 15) and therefore is an exciting avenue for future study. Our data are the first to measure metabolic parameters in our previously validated conditional spinophilin KO mice (29) and our current study demonstrates the need for cell type-specific approaches to fully understand spinophilin-dependent regulation of metabolism and cellular function.…”

Section: Discussionmentioning

confidence: 76%

“…Our data are the first to measure metabolic parameters in our previously validated conditional spinophilin KO mice (29) and our current study demonstrates the need for cell type-specific approaches to fully understand spinophilin-dependent regulation of metabolism and cellular function.…”

Section: Discussionmentioning

confidence: 80%

“…Spinophilin is expressed in islets and loss of spinophilin globally improves pancreatic metabolic parameters such as glucose tolerance. To detail if loss of spinophilin specifically in pancreatic beta cells impacts GTT, we utilized our recently described conditional spinophilin knockout mice (Spino fl/fl ) (29) and crossed them with Ins1Cre mice to knockout spinophilin specifically in pancreatic beta cells (Spino ΔIns ). Spino ΔIns mice, compared to control (Spino fl/fl and Ins1Cre), had improved glucose tolerance at 6 and 10 weeks ( Figure 6 B, C, H, I ) with no change in body weight ( Figure 6 D, G, J ).…”

Section: Resultsmentioning

confidence: 99%

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Mechanisms of spinophilin-dependent pancreas dysregulation underlying diabesity

Stickel

Mosley

Doud

et al. 2023

Preprint

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Objective: Spinophilin is an F-actin binding and protein phosphatase 1 (PP1) targeting protein that acts as a scaffold of PP1 to its substrates. Spinophilin knockout (Spino-/-) mice have decreased fat mass, increased lean mass, and improved glucose tolerance, with no difference in feeding behaviors. While spinophilin is enriched in neurons, its roles in non-neuronal tissues, such as beta cells of the pancreatic islets, are unclear. Methods & Results: We have corroborated and expanded upon previous studies to determine that Spino-/- mice have decreased weight gain and improved glucose tolerance in two different models of obesity. Using proteomics and immunoblotting-based approaches we identified multiple putative spinophilin interacting proteins isolated from intact pancreas and observed increased interactions of spinophilin with exocrine, ribosomal, and cytoskeletal protein classes that mediate peptide hormone production, processing, and/or release in Leprdb/db and/or high fat-fed (HFF) models of obesity. Moreover, loss of spinophilin specifically in pancreatic beta cells improved glucose tolerance without impacting body weight. Conclusion: Our data further support a role for spinophilin in mediating pathophysiological changes in body weight and whole-body metabolism associated with obesity and provide the first evidence that spinophilin mediates obesity-dependent pancreatic dysfunction that leads to deficits in glucose homeostasis or diabesity.

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Section: Discussionmentioning

confidence: 76%

Section: Discussionmentioning

confidence: 80%

Section: Resultsmentioning

confidence: 99%

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Mechanisms of spinophilin-dependent pancreas dysregulation underlying diabesity

Stickel

Mosley

Doud

et al. 2023

Preprint

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Spinophilin‐dependent regulation of GluN2B‐containing NMDAR‐dependent calcium influx, GluN2B surface expression, and cleaved caspase expression

Salek

Claeboe

Bansal

et al. 2023

Synapse

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N‐methyl‐d‐aspartate receptors (NMDARs) are calcium‐permeable ion channels that are ubiquitously expressed within the glutamatergic postsynaptic density. Phosphorylation of NMDAR subunits defines receptor conductance and surface localization, two alterations that can modulate overall channel activity. Modulation of NMDAR phosphorylation by kinases and phosphatases regulates the amount of calcium entering the cell and subsequent activation of calcium‐dependent processes. The dendritic spine enriched protein, spinophilin, is the major synaptic protein phosphatase 1 (PP1) targeting protein. Depending on the substrate, spinophilin can act as either a PP1 targeting protein, to permit substrate dephosphorylation, or a PP1 inhibitory protein, to enhance substrate phosphorylation. Spinophilin limits NMDAR function in a PP1‐dependent manner. Specifically, we have previously shown that spinophilin sequesters PP1 away from the GluN2B subunit of the NMDAR, which results in increased phosphorylation of Ser‐1284 on GluN2B. However, how spinophilin modifies NMDAR function is unclear. Herein, we utilize a Neuro2A cell line to detail that Ser‐1284 phosphorylation increases calcium influx via GluN2B‐containing NMDARs. Moreover, overexpression of spinophilin decreases GluN2B‐containing NMDAR activity by decreasing its surface expression, an effect that is independent of Ser‐1284 phosphorylation. In hippocampal neurons isolated from spinophilin knockout animals, there is an increase in cleaved caspase‐3 levels, a marker of calcium‐associated apoptosis, compared with wildtype mice. Taken together, our data demonstrate that spinophilin regulates GluN2B containing NMDAR phosphorylation, channel function, and trafficking and that loss of spinophilin enhances neuronal cleaved caspase‐3 expression.

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