SGIP1 is involved in regulation of emotionality, mood, and nociception and modulates in vivo signalling of cannabinoid CB<sub>1</sub> receptors

Dvořáková, Michaela; Kubik-Zahorodna, Agnieszka; Straiker, Alex; Sedláček, Radislav; Hájková, Alena; Blahoš, Jaroslav

doi:10.1111/bph.15383

Cited by 25 publications

(23 citation statements)

References 80 publications

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“…Multiple genes identified in both cohorts were relevant to dopaminergic signaling, including the dopamine D2 receptor subunit ( DRD2 ) and phosphodiesterase 4-beta ( PDE4B ) as well as a protein kinase A subunit ( PRKAR2A ) from MVP, which can subsequently modulate cAMP/CREB-mediated transcription of genes important for synaptic plasticity 13 . Additionally, SGIP1 was retained by GRIN in MVP and SA-EUR summary statistics, which affects presynaptic vesicle release and emotional state 14,15 . Furthermore, genes involved in neurotransmitter release ( BRSK1 ) and glutamatergic synapses ( CELSR3 16 ) were identified along with ICE2 , which is induced by NMDA receptor activity 17,18 .…”

Section: Resultsmentioning

confidence: 99%

Digging deeper into GWAS signal using GRIN implicates additional genes contributing to suicidal behavior

Sullivan

Lane

Cashman

et al. 2022

Preprint

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Genome-wide association studies (GWAS) identify genetic variants underlying complex traits but are limited by stringent genome-wide significance thresholds. Here we dramatically relax GWAS stringency by orders of magnitude and apply GRIN (Gene set Refinement through Interacting Networks), which increases confidence in the expanded gene set by retaining genes strongly connected by biological networks from diverse lines of evidence. From multiple GWAS summary statistics of suicide attempt, a complex psychiatric phenotype, GRIN identified additional genes that replicated across independent cohorts and retained genes that were more biologically interrelated despite a relaxed significance threshold. We present a conceptual model of how these retained genes interact through neurobiological pathways to influence suicidal behavior and identify existing drugs associated with these pathways that would not have been identified under traditional GWAS thresholds. We demonstrate that GRIN is a useful community resource for improving the signal to noise ratio of GWAS results.

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Section: Resultsmentioning

confidence: 99%

Digging deeper into GWAS signal using GRIN implicates additional genes contributing to suicidal behavior

Sullivan

Lane

Cashman

et al. 2022

Preprint

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“…Surprisingly, we have found that most previous studies regarding SGIP1 either inadvertently used SGIP1 instead of SGIP1α or used different SGIP1 isoforms indiscriminately (Supplementary Table S1). For example (854 a.a.) (Hollopeter et al, 2014;Dvorakova et al, 2021;Mishra et al, 2021) and (806 a.a) (Reider et al, 2009;Stimpson et al, 2009;Henne et al, 2010;Umasankar et al, 2014;Hájková et al, 2016;Ma et al, 2016) mouse SGIP1 isoforms were used indiscriminately in many studies, although the 806 isoform lacks the additional regions in the MP and C-terminal regions. In addition, in humans, instead of the 859 a.a. isoform that contains both additional regions listed above, an (828 a.a.) (Trevaskis et al, 2005;Dergai et al, 2010;Shimada et al, 2016;Petko et al, 2018;Zhang et al, 2018) isoform that lacks the above additional region in the MP domain was used without distinction in many studies.…”

Section: Introduction and Resultsmentioning

confidence: 99%

SGIP1α, but Not SGIP1, is an Ortholog of FCHo Proteins and Functions as an Endocytic Regulator

Lee

Cho

Jeong

et al. 2021

Front. Cell Dev. Biol.

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Src homology 3-domain growth factor receptor-bound 2-like interacting protein 1 (SGIP1), originally known as a regulator of energy homeostasis, was later found to be an ortholog of Fer/Cip4 homology domain-only (FCHo) proteins and to function during endocytosis. SGIP1α is a longer splicing variant in mouse brains that contains additional regions in the membrane phospholipid-binding domain (MP) and C-terminal region, but functional consequences with or without additional regions between SGIP1 and SGIP1α remain elusive. Moreover, many previous studies have either inadvertently used SGIP1 instead of SGIP1α or used the different isoforms with or without additional regions indiscriminately, resulting in further confusion. Here, we report that the additional region in the MP is essential for SGIP1α to deform membrane into tubules and for homo-oligomerization, and SGIP1, which lacks this region, fails to perform these functions. Moreover, only SGIP1α rescued endocytic defects caused by FCHo knock-down. Thus, our results indicate that SGIP1α, but not SGIP1, is the functional ortholog of FCHos, and SGIP1 and SGIP1α are not functionally redundant. These findings suggest that caution should be taken in interpreting the role of SGIP1 in endocytosis.

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“…In our previous study, we observed an altered development of tolerance to chronic treatment with THC in SGIP1 knock out mice compared with wild‐type mice in selected tasks (cannabinoid tetrad tests: (catalepsy, anti‐nociception, hypothermia, and suppression of motor coordination). Moreover, withdrawal signs were atypical the in absence of SGIP1 in the knock out animals (Dvorakova et al, 2021). CB1 receptor signaling is tightly regulated.…”

Section: Introductionmentioning

confidence: 99%

“…Intriguingly, different from other GPCRs, CB1R internalization is tightly controlled by interaction with the protein Src homology 3‐domain growth factor receptor‐bound 2‐like endophilin interacting protein 1 (SGIP1) (Dvorakova et al, 2021; Hajkova et al, 2016). SGIP1 together with FCH/F‐BAR domain only protein 1 and 2 (FCHO1/2) belong to muniscin family of proteins involved in GPCR internalization.…”

Section: Introductionmentioning

confidence: 99%

“…Here we aimed to study if β‐arrestin2 binding to the activated CB1R is dependent on GRK2/3 activity that phosphorylates the CB1R C‐tail in both motifs, and if GRK3 association with the receptor is also controlled by the phosphorylation of these motifs. In the presence of SGIP1, internalization of CB1R is hindered, with profound functional and behavioral consequences (Dvorakova et al, 2021; Hajkova et al, 2016).…”

Section: Introductionmentioning

confidence: 99%

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SGIP1 modulates kinetics and interactions of the cannabinoid receptor 1 and G protein‐coupled receptor kinase 3 signalosome

Gazdarica

Noda

Durydivka

et al. 2022

Journal of Neurochemistry

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Cannabinoid receptor 1 (CB1R), a G protein‐coupled receptor, plays a fundamental role in synaptic plasticity. Abnormal activity and deregulation of CB1R signaling result in a broad spectrum of pathological conditions. CB1R signaling is regulated by receptor desensitization including phosphorylation of residues within the intracellular C terminus by G protein‐coupled receptor kinases (GRKs) that may lead to endocytosis. Furthermore, CB1R signaling is regulated by the protein Src homology 3‐domain growth factor receptor‐bound 2‐like (SGIP1) that hinders receptor internalization, while enhancing CB1R association with β‐arrestin. It has been postulated that phosphorylation of two clusters of serine/threonine residues, 425SMGDS429 and 460TMSVSTDTS468, within the CB1R C‐tail controls dynamics of the association between receptor and its interaction partners involved in desensitization. Several molecular determinants of these events are still not well understood. We hypothesized that the dynamics of these interactions are modulated by SGIP1. Using a panel of CB1Rs mutated in the aforementioned serine and threonine residues, together with an array of Bioluminescence energy transfer‐based (BRET) sensors, we discovered that GRK3 forms complexes with Gβγ subunits of G proteins that largely independent of GRK3’s interaction with CB1R. Furthermore, CB1R interacts only with activated GRK3. Interestingly, phosphorylation of two specific residues on CB1R triggers GRK3 dissociation from the desensitized receptor. SGIP1 increases the association of GRK3 with Gβγ subunits of G proteins, and with CB1R. Altogether, our data suggest that the CB1R signalosome complex is dynamically controlled by sequential phosphorylation of the receptor C‐tail and is also modified by SGIP1.

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SGIP1 is involved in regulation of emotionality, mood, and nociception and modulates in vivo signalling of cannabinoid CB₁ receptors

Abstract: SGIP1 is involved in regulation of emotionality, mood, and nociception and tunes in vivo signaling of Cannabinoid Receptor 1

Cited by 25 publications

References 80 publications

Digging deeper into GWAS signal using GRIN implicates additional genes contributing to suicidal behavior

Digging deeper into GWAS signal using GRIN implicates additional genes contributing to suicidal behavior

SGIP1α, but Not SGIP1, is an Ortholog of FCHo Proteins and Functions as an Endocytic Regulator

SGIP1 modulates kinetics and interactions of the cannabinoid receptor 1 and G protein‐coupled receptor kinase 3 signalosome

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SGIP1 is involved in regulation of emotionality, mood, and nociception and modulates in vivo signalling of cannabinoid CB1 receptors

Abstract: SGIP1 is involved in regulation of emotionality, mood, and nociception and tunes in vivo signaling of Cannabinoid Receptor 1

Cited by 25 publications

References 80 publications

Digging deeper into GWAS signal using GRIN implicates additional genes contributing to suicidal behavior

Digging deeper into GWAS signal using GRIN implicates additional genes contributing to suicidal behavior

SGIP1α, but Not SGIP1, is an Ortholog of FCHo Proteins and Functions as an Endocytic Regulator

SGIP1 modulates kinetics and interactions of the cannabinoid receptor 1 and G protein‐coupled receptor kinase 3 signalosome

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SGIP1 is involved in regulation of emotionality, mood, and nociception and modulates in vivo signalling of cannabinoid CB₁ receptors