Farnesylation of the Transducin G Protein Gamma Subunit Is a Prerequisite for Its Ciliary Targeting in Rod Photoreceptors

Brooks, Celine; Murphy, Joseph; Belcastro, Marycharmain; Heller, Daniel; Kolandaivelu, Saravanan; Kisselev, Oleg G.; Sokolov, Maxim

doi:10.3389/fnmol.2018.00016

Cited by 17 publications

(13 citation statements)

References 48 publications

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“…To examine whether the protein level of syntaxin-3 corresponds with the mRNA level in CA1 neurons, we performed immunofluorescence microscopy of the hippocampus. We used a polyclonal antibody that has been successfully used in previous studies [24][25][26] to detect syntaxin-3 in mouse photoreceptor cells. This antibody failed to detect syntaxin-3 in the CA1 neurons ( Supplementary Fig.…”

Section: Low Syntaxin-3 Mrna and Protein Expression In Hippocampal Anmentioning

confidence: 99%

Syntaxin-3 is dispensable for basal neurotransmission and synaptic plasticity in postsynaptic hippocampal CA1 neurons

Shi

Harada

et al. 2020

Sci Rep

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Recent evidence suggests that SNARE fusion machinery play critical roles in postsynaptic neurotransmitter receptor trafficking, which is essential for synaptic plasticity. However, the key SNAREs involved remain highly controversial; syntaxin-3 and syntaxin-4 are leading candidates for the syntaxin isoform underlying postsynaptic plasticity. In a previous study, we showed that pyramidalneuron specific conditional knockout (cKO) of syntaxin-4 significantly reduces basal transmission, synaptic plasticity and impairs postsynaptic receptor trafficking. However, this does not exclude a role for syntaxin-3 in such processes. Here, we generated and analyzed syntaxin-3 cKO mice. Extracellular field recordings in hippocampal slices showed that syntaxin-3 cKO did not exhibit significant changes in CA1 basal neurotransmission or in paired-pulse ratios. Importantly, there were no observed differences during LTP in comparison to control mice. Syntaxin-3 cKO mice performed similarly as the controls in spatial and contextual learning tasks. Consistent with the minimal effects of syntaxin-3 cKO, syntaxin-3 mRNA level was very low in hippocampal and cortex pyramidal neurons, but strongly expressed in the corpus callosum and caudate axon fibers. Together, our data suggest that syntaxin-3 is dispensable for hippocampal basal neurotransmission and synaptic plasticity, and further supports the notion that syntaxin-4 is the major isoform mediating these processes.Synaptic transmission is essential for neuronal communication in the brain. During synaptic transmission, presynaptic neurons release neurotransmitters that bind to their respective receptors on the postsynaptic membrane. Ionotropic glutamate receptors (AMPARs and NMDARs) and GABA receptors on the postsynaptic membrane undergo receptor recycling. Receptor recycling is an essential process in synaptic plasticity such as long-term potentiation (LTP). LTP is a cellular correlate for higher-level cognitive functions of learning and memory 1-5 and requires rapid modifications in the quantity and composition of postsynaptic glutamate receptors 4,6,7 . Despite its importance, the underlying mechanisms of postsynaptic membrane receptor trafficking still remain unclear.Postsynaptic receptor trafficking employs a unique soluble NSF-attachment protein receptor (SNARE) complex that mediates the attachment and fusion of vesicles containing postsynaptic receptors to target membranes. The SNARE complex is composed of one vesicle membrane protein (v-SNARE; synaptobrevin) and two target membrane proteins (t-SNAREs; syntaxin and SNAP-25 isoforms) 8 . Botulinum neurotoxin B (BoNT/B) proteolyzes synaptobrevin-2 and when injected into CA1 pyramidal cells, blocks LTP induction 9 . This suggests that this open Scientific RepoRtS | (2020) 10:709 | https://doi.org/10.1038/s41598-019-57388-6www.nature.com/scientificreports www.nature.com/scientificreports/ v-SNARE is imperative for AMPAR delivery to the postsynaptic membrane during LTP. However, the particular isoforms of t-SNAREs involved in postsyna...

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Section: Low Syntaxin-3 Mrna and Protein Expression In Hippocampal Anmentioning

confidence: 99%

Syntaxin-3 is dispensable for basal neurotransmission and synaptic plasticity in postsynaptic hippocampal CA1 neurons

Shi

Harada

et al. 2020

Sci Rep

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“…GNG5 encodes a member of G protein, which plays a critical role in internalization, trafficking, and signaling pathways of various G-protein coupled receptors [10]. As shown in previous studies, G-protein could induce apoptotic response in various cancers, such as murine colon adenocarcinoma, human melanoma cells [11,12].…”

Section: Discussionmentioning

confidence: 99%

Identification of candidate biomarkers associated with apoptosis in melanosis coli: GNG5, LPAR3, MAPK8, and PSMC6

Hua

Chen

2019

Bioscience Reports

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Purpose: Melanosis coli (MC) is a disorder of pigmentation of the wall of the colon, often identified at the time of colonoscopy. The aim of the present study is to identify candidate biomarkers for MC. Methods: The transcriptome data for MC (GSE78933) with five MC tissues and five corresponding normal tissues is obtained from the NCBI Gene Expression Omnibus (GEO) database. R/Bioconductor package limma was used to screen differently expressed genes (DEGs). ClueGO of cytoscape was applied for Gene Ontology (GO) functional and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment. Based on STRING V10 database, protein–protein interaction (PPI) network was constructed. The pathological tissue and normal tissue from 23 MC patients and 23 controls were collected, respectively. The relative expression of hub nodes was detected by qRT-PCR and Western blot. For regulating the expression of these genes, overexpression vector was constructed or siRNA transfection was used. Finally, apoptosis was detected by flow cytometry. Results: Total 1342 DEGs were screened, including 786 up-regulated and 556 down-regulated genes. These genes were mainly enriched in stimulatory C-type lectin receptor signaling pathway, polysaccharide biosynthetic process, intracellular, and oxidative phosphorylation. PPI network was then constructed with 426 DEGs and 895 interactions. Thereinto, G-protein subunit γ 5 (GNG5), lysophosphatidic acid receptor 3 (LPAR3), mitogen-activated protein kinase 8 (MAPK8), NHP2L1, proteasome 26S subunit, ATPase 6 (PSMC6), and phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit β (PIK3CB) were hub nodes with higher degree. RT-PCR and Western blot results showed that GNG5, LPAR3, MAPK8, and PSMC6 were differently expressed with significance. The expression of these screened genes is also related with cell apoptosis. Conclusion: GNG5, LPAR3, MAPK8, and PSMC6 might be candidate biomarkers associated with apoptosis in MC.

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“…Ca 2+ -induced apoptosis will result (Orrenius et al, 2003). Other mechanisms have since been suggested, e.g., Kowluru (2017) and Brooks et al (2018).…”

Section: Why Is Farnesol Such a “Noble Unknown” In (Mainly Vertebratementioning

confidence: 99%

“…To date, despite the progress obtained in recent high resolution structural studies (Thal et al, 2018), it is not yet fully understood how allosteric transitions (conformational 3D changes) caused by binding of, e.g., a ligand to the binding pocket of a GPCR finally yield a physiological effect inside the cell. Particularly, the role of prenylation remains enigmatic, despite some recent progress in diabetes research (Kowluru, 2017), and in uncovering the role of farnesylation of the transducing γ subunit as a prerequisite for its ciliary targeting (i.e., to outer segments of vertebrate rod photoreceptors) (Brooks et al, 2018).…”

Section: The Main Bottleneck In Understanding Gpcrs: Intrinsically Almentioning

confidence: 99%

Flip-Flopping Retinal in Microbial Rhodopsins as a Template for a Farnesyl/Prenyl Flip-Flop Model in Eukaryote GPCRs

Loof

Schoofs

2019

Front. Neurosci.

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Thirty years after the first description and modeling of G protein coupled receptors (GPCRs), information about their mode of action is still limited. One of the questions that is hard to answer is: how do the allosteric changes in the GPCR induced by, e.g., ligand binding in the end activate a G protein-dependent intracellular pathway (e.g., via the cAMP or the phosphatidylinositol signal pathways). Another question relates to the role of prenylation of G proteins. Today’s “consensus model” states that protein prenylation is required for the assembly of GPCR-G protein complexes. Although it is well-known that protein prenylation is the covalent addition of a farnesyl- or geranylgeranyl moiety to the C terminus of specific proteins, e.g., α or γ G protein, the reason for this strong covalent binding remains enigmatic. The arguments for a fundamental role for prenylation of G proteins other than just being a hydrophobic linker, are gradually accumulating. We uncovered a dilemma that at first glance may be considered physiologically irrelevant, however, it may cause a true change in paradigm. The consensus model suggests that the only functional role of prenylation is to link the G protein to the receptor. Does the isoprenoid nature of the prenyl group and its exact site of attachment somehow matter? Or, are there valid arguments favoring the alternative possibility that a key role of the G protein is to guide the covalently attached prenyl group to – and it hold it in – a very specific location in between specific helices of the receptor? Our model says that the farnesyl/prenyl group – aided by its covalent attachment to a G protein -might function in GPCRs as a horseshoe-shaped flexible (and perhaps flip-flopping) hydrophobic valve for restricting (though not fully inhibiting) the untimely passage of Ca 2+ , like retinal does for the passage of H + in microbial rhodopsins that are ancestral to many GPCRs.

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Farnesylation of the Transducin G Protein Gamma Subunit Is a Prerequisite for Its Ciliary Targeting in Rod Photoreceptors

Cited by 17 publications

References 48 publications

Syntaxin-3 is dispensable for basal neurotransmission and synaptic plasticity in postsynaptic hippocampal CA1 neurons

Syntaxin-3 is dispensable for basal neurotransmission and synaptic plasticity in postsynaptic hippocampal CA1 neurons

Identification of candidate biomarkers associated with apoptosis in melanosis coli: GNG5, LPAR3, MAPK8, and PSMC6

Flip-Flopping Retinal in Microbial Rhodopsins as a Template for a Farnesyl/Prenyl Flip-Flop Model in Eukaryote GPCRs

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