Molecular and Cellular Neuroscience最新文献

{"title":"Role of ALS-associated OPTN-K489E mutation in neuronal cell-death regulation","authors":"Dibyakanti Mishra ,&nbsp;Priyam Narain ,&nbsp;Upma Dave ,&nbsp;James Gomes","doi":"10.1016/j.mcn.2023.103904","DOIUrl":"10.1016/j.mcn.2023.103904","url":null,"abstract":"<div><p>Optineurin (<em>OPTN)</em> gene is a marker of amyotrophic lateral sclerosis (ALS). However, the role of optineurin protein (OPTN) in ALS pathology is unclear, even though it is known to regulate autophagy, apoptosis, and other survival-death cellular processes. Genetic analysis of Indian ALS patients by our group ascertained a novel mutation K489E in the <em>OPTN</em> gene. To identify the molecular mechanism associated with OPTN and its mutation, we developed an in-vitro cell model using SH-SY5Y cells harbouring OPTN and OPTN-K489E mutation along with its control vector. Since we observed a significant decrease in cell viability in the mutant, we measured the expressions of genes and proteins mediating apoptosis, necroptosis, and autophagy, to establish the role of OPTN in cell death regulation. Our results show that OPTN-K489E mutation changes the relative gene expressions of miRNA-9, REST, CoREST and BDNF, and causes apoptosis. We also observed an up-regulation in the expressions of necroptosis mediated genes RIPK1, RIPK3, and MLKL and autophagy mediated genes TBK1, P62, and LC3II. The results of FACS analyses revealed that this mutation promotes apoptotic and necroptotic processes confirming the pathogenicity of OPTN-K489E.</p></div>","PeriodicalId":18739,"journal":{"name":"Molecular and Cellular Neuroscience","volume":"127 ","pages":"Article 103904"},"PeriodicalIF":3.5,"publicationDate":"2023-10-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"71424955","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The NIDA Avenir award in genetics or epigenetics of substance use disorders","authors":"John S. Satterlee ,&nbsp;Jonathan D. Pollock ,&nbsp;Nora D. Volkow","doi":"10.1016/j.mcn.2023.103899","DOIUrl":"10.1016/j.mcn.2023.103899","url":null,"abstract":"<div><p>NIDA's Avenir Program in the Genetics<span> or Epigenetics of Substance Use Disorders (SUDs) was launched to support early stage investigators who propose innovative, high risk, but potentially high impact research and who show promise of being tomorrow's leaders in this scientific field. Since 2015, NIDA has supported 30 Avenir Investigators with unique expertise and creative ideas. This special issue showcases how some of these ideas have germinated, flourished, and borne fruit. In this perspective article we briefly describe the purpose and implementation of the Avenir award and provide a high altitude overview of the awardees and their scientific projects to date.</span></p></div>","PeriodicalId":18739,"journal":{"name":"Molecular and Cellular Neuroscience","volume":"127 ","pages":"Article 103899"},"PeriodicalIF":3.5,"publicationDate":"2023-09-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41134748","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The intrinsic apoptotic pathway lies upstream of reactive species production in cortical neurons and age-related oxidative stress in the brain","authors":"Kyndra Stovall ,&nbsp;Mital Patel ,&nbsp;James L. Franklin","doi":"10.1016/j.mcn.2023.103901","DOIUrl":"10.1016/j.mcn.2023.103901","url":null,"abstract":"<div><p><span><span>A BAX- and mitochondria-dependent production of reactive oxygen species (ROS) and reactive species (reactive nitrogen species, RNS) lying downstream of these ROS occurs in apoptotic and nonapoptotic mouse sympathetic neurons and cerebellar </span>granule cells<span> in cell culture. These ROS have been shown to lie downstream of caspase 3<span><span> in mouse sympathetic neurons. Here we show that BAX is necessary for similar ROS production in apoptotic and nonapoptotic mouse cortical neurons in cell culture and that it also positively regulates oxidative stress<span><span> in the brains of mice of different ages. Brains from mice with genetically reduced levels of mitochondrial superoxide dismutase 2 (SOD2) exhibited elevated levels of </span>DNA strand breaks consistent with oxidative damage. </span></span>Lipid peroxides<span> were also elevated at some ages in comparison to the brains of wild type animals. BAX deletion in these mice reduced both brain DNA strand breaks and lipid peroxide levels to well below those of wild type animals. Deletion of caspase 3 greatly reduced age-augmented levels of brain oxidative stress markers including lipid peroxides, oxidized DNA, and nitrosylated proteins. These findings indicate that BAX contributes to ROS production in mouse cortical neurons, to oxidative stress their brains, and that this effect is likely mediated </span></span></span></span><em>via</em> caspase 3 activity.</p></div>","PeriodicalId":18739,"journal":{"name":"Molecular and Cellular Neuroscience","volume":"127 ","pages":"Article 103901"},"PeriodicalIF":3.5,"publicationDate":"2023-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41104817","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Efferent axons in the zebrafish lateral line degenerate following sensory hair cell ablation","authors":"Melek Umay Tuz-Sasik,&nbsp;Remy Manuel,&nbsp;Henrik Boije","doi":"10.1016/j.mcn.2023.103900","DOIUrl":"10.1016/j.mcn.2023.103900","url":null,"abstract":"<div><p>The zebrafish lateral line is a frequently used model to study the mechanisms behind peripheral neuronal innervation of sensory organs and the regeneration thereof. The lateral line system consists of neuromasts, a cluster of protruding hair cells, which are innervated by sensory afferent and modulatory efferent neurons. These flow-sensing hair cells are similar to the hair cells in the mammalian ear. Though, while hair cell loss in humans is irreversible, the zebrafish neuromasts are regarded as the fastest regenerating structure in vertebrates, making them an ideal model to study regeneration. However, one component of the lateral line system, the efferent projections, has largely been omitted in regenerative studies. Here, for the first time, we bring insights into the fate of efferent axons during ablation and regeneration of the hair cells in the zebrafish lateral line. Our behavioral analysis showed functional recovery of hair cells and sensory transmission within 48 h and their regeneration were in line with previous studies. Analysis of the inhibitory efferent projections revealed that in approximately half the cases the inhibitory efferent axons degenerated, which was never observed for the sensory afferent axons. Quantification of hair cells following ablation suggests that the presence of mature hair cells in the neuromast may prevent axon degeneration. Within 120 h, degenerated efferent axons regenerated along the axonal tract of the lateral line. Reanalysis of published single cell neuromast data hinted to a role for Bdnf in the survival of efferent axons. However, sequestering Bdnf, blocking the Trk-receptors, and inhibiting the downstream ERK-signaling, did not induce axon degeneration, indicating that efferent survival is not mediated through neurotrophic factors. To further explore the relation between hair cells and efferent projections, we generated <em>atoh1a</em> mutants, where mature hair cells never form. In larvae lacking hair cells, inhibitory efferent projections were still present, following the tract of the sensory afferent without displaying any innervation. Our study reveal the fate of efferent innervation following hair cell ablation and provide insights into the inherent differences in regeneration between neurons in the peripheral and central nervous system.</p></div>","PeriodicalId":18739,"journal":{"name":"Molecular and Cellular Neuroscience","volume":"127 ","pages":"Article 103900"},"PeriodicalIF":3.5,"publicationDate":"2023-09-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10288761","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Proglucagon signalling in the rat Dorsomedial Hypothalamus – Physiology and high-fat diet-mediated alterations","authors":"A.M. Sanetra ,&nbsp;K. Palus-Chramiec ,&nbsp;L. Chrobok ,&nbsp;J.S. Jeczmien-Lazur ,&nbsp;J.D. Klich ,&nbsp;M.H. Lewandowski","doi":"10.1016/j.mcn.2023.103873","DOIUrl":"10.1016/j.mcn.2023.103873","url":null,"abstract":"<div><p>A relatively new pharmacological target in obesity treatment has been the preproglucagon (PPG) signalling, predominantly with glucagon-like peptide (GLP) 1 receptor agonists. As far as the PPG role within the digestive system is well recognised, its actions in the brain remain understudied. Here, we investigated PPG signalling in the Dorsomedial Hypothalamus (DMH), a structure involved in feeding regulation and metabolism, using in situ hybridisation, electrophysiology, and immunohistochemistry. Our experiments were performed on animals fed both control, and high-fat diet (HFD), uncovering HFD-mediated alterations. First, sensitivity to exendin-4 (Exn4, a GLP1R agonist) was shown to increase under HFD, with a higher number of responsive neurons. The amplitude of the response to both Exn4 and oxyntomodulin (Oxm) was also altered, diminishing its relationship with the cells' spontaneous firing rate. Not only neuronal sensitivity, but also GLP1 presence, and therefore possibly release, was influenced by HFD. Immunofluorescent labelling of the GLP1 showed changes in its density depending on the metabolic state (fasted/fed), but this effect was eliminated by HFD feeding. Interestingly, these dietary differences were absent after a period of restricted feeding, allowing for an anticipation of the alternating metabolic states, which suggests possible prevention of such outcome.</p></div>","PeriodicalId":18739,"journal":{"name":"Molecular and Cellular Neuroscience","volume":"126 ","pages":"Article 103873"},"PeriodicalIF":3.5,"publicationDate":"2023-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10166554","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The long-loop recycling (LLR) of synaptic components as a question of economics","authors":"Svilen Veselinov Georgiev ,&nbsp;Silvio O. Rizzoli","doi":"10.1016/j.mcn.2023.103862","DOIUrl":"10.1016/j.mcn.2023.103862","url":null,"abstract":"<div><p>The pre- and post-synaptic compartments contain a variety of molecules that are known to recycle between the plasma membrane and intracellular organelles. The recycling steps have been amply described in functional terms, with, for example, synaptic vesicle recycling being essential for neurotransmitter release, and postsynaptic receptor recycling being a fundamental feature of synaptic plasticity. However, synaptic protein recycling may also serve a more prosaic role, simply ensuring the repeated use of specific components, thereby minimizing the energy expenditure on the synthesis of synaptic proteins. This type of process has been recently described for components of the extracellular matrix, which undergo long-loop recycling (LLR), to and from the cell body. Here we suggest that the energy-saving recycling of synaptic components may be more widespread than is generally acknowledged, potentially playing a role in both synaptic vesicle protein usage and postsynaptic receptor metabolism.</p></div>","PeriodicalId":18739,"journal":{"name":"Molecular and Cellular Neuroscience","volume":"126 ","pages":"Article 103862"},"PeriodicalIF":3.5,"publicationDate":"2023-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10519324","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Systemic inflammation induced from remote extremity trauma is a critical driver of secondary brain injury","authors":"Cassie J. Rowe ,&nbsp;Josef Mang ,&nbsp;Benjamin Huang ,&nbsp;Kalpana Dommaraju ,&nbsp;Benjamin K. Potter ,&nbsp;Seth A. Schobel ,&nbsp;Eric R. Gann ,&nbsp;Thomas A. Davis","doi":"10.1016/j.mcn.2023.103878","DOIUrl":"10.1016/j.mcn.2023.103878","url":null,"abstract":"<div><p><span><span><span>Blast exposure, commonly experienced by military personnel, can cause devastating life-threatening polysystem trauma. Despite considerable research efforts, the impact of the systemic inflammatory response after major trauma on secondary brain injury-inflammation is largely unknown. The aim of this study was to identify markers underlying the susceptibility and early onset of neuroinflammation in three rat trauma models: (1) blast overpressure exposure (BOP), (2) complex extremity trauma (CET) involving femur fracture, crush injury, tourniquet-induced ischemia, and transfemoral amputation through the fracture site, and (3) BOP+CET. Six hours post-injury, intact brains were harvested and dissected to obtain biopsies from the prefrontal cortex, striatum, neocortex, hippocampus, </span>amygdala<span>, thalamus, hypothalamus, and </span></span>cerebellum. Custom low-density microarray datasets were used to identify, interpret and visualize genes significant (</span><em>p</em><span><span><span> &lt; 0.05 for differential expression [DEGs]; 86 neuroinflammation-associated) using a custom python-based computer program, principal component analysis, heatmaps and volcano plots. Gene set and pathway enrichment analyses of the DEGs was performed using R and STRING for protein-protein interaction (PPI) to identify and explore key genes and signaling networks. Transcript profiles were similar across all regions in naïve brains with similar expression levels involving </span>neurotransmission and transcription functions and undetectable to low-levels of inflammation-related mediators. Trauma-induced neuroinflammation across all anatomical brain regions correlated with injury severity (BOP+CET &gt; CET &gt; BOP). The most pronounced differences in neuroinflammatory-neurodegenerative gene regulation were between blast-associated trauma (BOP, BOP+CET) and CET. Following BOP, there were few DEGs detected amongst all 8 brain regions, most were related to cytokines/chemokines and </span>chemokine receptors, where PPI analysis revealed </span><em>Il1b</em> as a potential central hub gene. In contrast, CET led to a more excessive and diverse pro-neuroinflammatory reaction in which <em>Il6</em> was identified as the central hub gene. Analysis of the of the BOP+CET dataset, revealed a more global heightened response (<em>Cxcr2</em>, <em>Il1b</em>, <em>and Il6</em>) as well as the expression of additional functional regulatory networks/hub genes (<em>Ccl2</em>, <em>Ccl3</em>, <em>and Ccl4</em><span>) which are known to play a critical role in the rapid recruitment and activation of immune cells via chemokine/cytokine signaling. These findings provide a foundation for discerning pathophysiological consequences of acute extremity injury and systemic inflammation following various forms of trauma in the brain.</span></p></div>","PeriodicalId":18739,"journal":{"name":"Molecular and Cellular Neuroscience","volume":"126 ","pages":"Article 103878"},"PeriodicalIF":3.5,"publicationDate":"2023-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10169050","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Glycogen phosphorylase isoenzyme GPbb versus GPmm regulation of ventromedial hypothalamic nucleus glucoregulatory neurotransmitter and counter-regulatory hormone profiles during hypoglycemia: Role of L-lactate and octadecaneuropeptide","authors":"Md. Main Uddin ,&nbsp;Md. Haider Ali ,&nbsp;A.S.M.H. Mahmood ,&nbsp;Khaggeswar Bheemanapally ,&nbsp;Jérôme Leprince ,&nbsp;Karen P. Briski","doi":"10.1016/j.mcn.2023.103863","DOIUrl":"10.1016/j.mcn.2023.103863","url":null,"abstract":"<div><p><span><span>Glucose accesses the brain primarily via the astrocyte cell compartment, where it passes through the glycogen shunt before catabolism to the oxidizable fuel L-lactate. Glycogen phosphorylase (GP) </span>isoenzymes<span><span> GPbb and GPmm impose distinctive control of ventromedial hypothalamic nucleus (VMN) glucose-regulatory neurotransmission during hypoglycemia, but lactate and/or </span>gliotransmitter<span><span> involvement in those actions is unknown. Lactate or the octadecaneuropeptide </span>receptor antagonist cyclo(1–8)[DLeu</span></span></span>⁵<span><span>] OP (LV-1075) did not affect gene product down-regulation caused by GPbb or GPmm siRNA<span>, but suppressed non-targeted GP variant expression in a VMN region-specific manner. Hypoglycemic up-regulation of neuronal nitric oxide synthase was enhanced in rostral and caudal VMN by GPbb knockdown, yet attenuated by GPMM siRNA in the middle VMN; lactate or LV-1075 reversed these silencing effects. Hypoglycemic inhibition of </span></span>glutamate decarboxylase65/67 was magnified by GPbb (middle and caudal VMN) or GPmm (middle VMN) knockdown, responses that were negated by lactate or LV-1075. GPbb or GPmm siRNA enlarged hypoglycemic VMN glycogen profiles in rostral and middle VMN. Lactate and LV-1075 elicited progressive rostral VMN glycogen augmentation in GPbb knockdown rats, but stepwise-diminution of rostral and middle VMN glycogen after GPmm silencing. GPbb, not GPmm, knockdown caused lactate or LV-1075 – reversible amplification of hypoglycemic hyperglucagonemia and hypercorticosteronemia. Results show that lactate and octadecaneuropeptide exert opposing control of GPbb protein in distinct VMN regions, while the latter stimulates GPmm. During hypoglycemia, GPbb and GPmm may respectively diminish (rostral, caudal VMN) or enhance (middle VMN) nitrergic transmission and each oppose GABAergic signaling (middle VMN) by lactate- and octadecaneuropeptide-dependent mechanisms.</span></p></div>","PeriodicalId":18739,"journal":{"name":"Molecular and Cellular Neuroscience","volume":"126 ","pages":"Article 103863"},"PeriodicalIF":3.5,"publicationDate":"2023-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10527669/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10156655","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Paternal morphine exposure in rats reduces social play in adolescent male progeny without affecting drug-taking behavior in juvenile males or female offspring","authors":"Dana Zeid ,&nbsp;Andre B. Toussaint ,&nbsp;Carmen C. Dressler ,&nbsp;Samuel P. Schumacher ,&nbsp;Chau Do ,&nbsp;Heather Desalvo ,&nbsp;Danait Selamawi ,&nbsp;Angela R. Bongiovanni ,&nbsp;Hannah L. Mayberry ,&nbsp;Gregory V. Carr ,&nbsp;Mathieu E. Wimmer","doi":"10.1016/j.mcn.2023.103877","DOIUrl":"10.1016/j.mcn.2023.103877","url":null,"abstract":"<div><p><span><span>The ongoing opioid addiction<span> crisis necessitates the identification of novel risk factors to improve prevention and treatment of opioid use disorder. Parental opioid exposure has recently emerged as a potential regulator of offspring vulnerability to opioid misuse, in addition to heritable genetic liability. An understudied aspect of this “missing heritability” is the developmental presentation of these cross-generational phenotypes. This is an especially relevant question in the context of inherited addiction-related phenotypes, given the prominent role of developmental processes in the etiology of psychiatric disorders. Paternal morphine self-administration was previously shown to alter the sensitivity to the reinforcing and antinociceptive properties of opioids in the next generation. Here, phenotyping was expanded to include the adolescent period, with a focus on </span></span>endophenotypes related to opioid use disorders and pain. Paternal morphine exposure did not alter heroin or cocaine self-administration in male and female juvenile progeny. Further, baseline sensory reflexes related to pain were unaltered in morphine-sired adolescent rats of either sex. However, morphine-sired adolescent males exhibited a reduction in social play </span>behavior. Our findings suggest that, in morphine-sired male offspring, paternal opioid exposure does not affect opioid intake during adolescence, suggesting that this phenotype does not emerge until later in life. Altered social behaviors in male morphine-sired adolescents indicate that the changes in drug-taking behavior in adults sired by morphine-exposed sires may be due to more complex factors not yet fully assessed.</p></div>","PeriodicalId":18739,"journal":{"name":"Molecular and Cellular Neuroscience","volume":"126 ","pages":"Article 103877"},"PeriodicalIF":3.5,"publicationDate":"2023-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10528482/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10165768","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The intracellular C-terminal domain of mGluR6 contains ER retention motifs","authors":"Atsushi Shimohata ,&nbsp;Dilip Rai ,&nbsp;Takumi Akagi,&nbsp;Sumiko Usui,&nbsp;Ikuo Ogiwara,&nbsp;Makoto Kaneda","doi":"10.1016/j.mcn.2023.103875","DOIUrl":"10.1016/j.mcn.2023.103875","url":null,"abstract":"<div><p>Metabotropic glutamate<span><span> receptor 6 (mGluR6) predominantly localizes to the postsynaptic sites of retinal ON-bipolar cells, at which it recognizes glutamate released from photoreceptors<span><span><span>. The C-terminal domain (CTD) of mGluR6 contains a cluster of basic amino acids resembling motifs for </span>endoplasmic reticulum<span> (ER) retention. We herein investigated whether these basic residues are involved in regulating the subcellular localization of mGluR6 in 293T cells expressing mGluR6 CTD mutants using </span></span>immunocytochemistry<span>, immunoprecipitation, and flow cytometry. We showed that full-length mGluR6 localized to the ER and cell surface, whereas mGluR6 mutants with 15- and 20-amino acid deletions from the C terminus localized to the ER, but were deficient at the cell surface. We also demonstrated that the cell surface deficiency of mGluR6 mutants was rescued by introducing an </span></span></span>alanine<span> substitution at basic residues within the CTD. The surface-deficient mGluR6 mutant still did not localize to the cell surface and was retained in the ER when co-expressed with surface-expressible constructs, including full-length mGluR6, even though surface-deficient and surface-expressible constructs formed heteromeric complexes. The co-expression of the surface-deficient mGluR6 mutant reduced the surface levels of surface-expressible constructs. These results indicate that basic residues in the mGluR6 CTD served as ER retention signals. We suggest that exposed ER retention motifs in the aberrant assembly containing truncated or misfolded mGluR6 prevent these protein complexes from being transported to the cell surface.</span></span></p></div>","PeriodicalId":18739,"journal":{"name":"Molecular and Cellular Neuroscience","volume":"126 ","pages":"Article 103875"},"PeriodicalIF":3.5,"publicationDate":"2023-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10168541","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}