Cognitive Impairment Induced by Delta9-tetrahydrocannabinol Occurs through Heteromers between Cannabinoid CB1 and Serotonin 5-HT2A Receptors
Events
Loading … Spinner

Mendeley | Further Information

{"title"=>"Cognitive Impairment Induced by Delta9-tetrahydrocannabinol Occurs through Heteromers between Cannabinoid CB1 and Serotonin 5-HT2A Receptors", "type"=>"journal", "authors"=>[{"first_name"=>"Xavier", "last_name"=>"Viñals"}, {"first_name"=>"Estefanía", "last_name"=>"Moreno"}, {"first_name"=>"Laurence", "last_name"=>"Lanfumey"}, {"first_name"=>"Arnau", "last_name"=>"Cordomí"}, {"first_name"=>"Antoni", "last_name"=>"Pastor"}, {"first_name"=>"Rafael", "last_name"=>"de La Torre"}, {"first_name"=>"Paola", "last_name"=>"Gasperini"}, {"first_name"=>"Gemma", "last_name"=>"Navarro"}, {"first_name"=>"Lesley A.", "last_name"=>"Howell"}, {"first_name"=>"Leonardo", "last_name"=>"Pardo"}, {"first_name"=>"Carmen", "last_name"=>"Lluís"}, {"first_name"=>"Enric I.", "last_name"=>"Canela"}, {"first_name"=>"Peter J.", "last_name"=>"McCormick"}, {"first_name"=>"Rafael", "last_name"=>"Maldonado"}, {"first_name"=>"Patricia", "last_name"=>"Robledo"}], "year"=>2015, "source"=>"PLOS Biology", "identifiers"=>{"sgr"=>"84938703167", "pmid"=>"26158621", "arxiv"=>"e1002194", "pui"=>"605486422", "isbn"=>"10.1371/journal.pbio.1002194", "doi"=>"10.1371/journal.pbio.1002194", "issn"=>"1545-7885"}, "id"=>"9ae85409-c4bc-31b8-ba3e-364166df75af", "abstract"=>"Activation of cannabinoid CB1 receptors (CB1R) by delta9-tetrahydrocannabinol (THC) produces a variety of negative effects with major consequences in cannabis users that constitute important drawbacks for the use of cannabinoids as therapeutic agents. For this reason, there is a tremendous medical interest in harnessing the beneficial effects of THC. Behavioral studies carried out in mice lacking 5-HT2A receptors (5-HT2AR) revealed a remarkable 5-HT2AR-dependent dissociation in the beneficial antinociceptive effects of THC and its detrimental amnesic properties. We found that specific effects of THC such as memory deficits, anxiolytic-like effects, and social interaction are under the control of 5-HT2AR, but its acute hypolocomotor, hypothermic, anxiogenic, and antinociceptive effects are not. In biochemical studies, we show that CB1R and 5-HT2AR form heteromers that are expressed and functionally active in specific brain regions involved in memory impairment. Remarkably, our functional data shows that costimulation of both receptors by agonists reduces cell signaling, antagonist binding to one receptor blocks signaling of the interacting receptor, and heteromer formation leads to a switch in G-protein coupling for 5-HT2AR from Gq to Gi proteins. Synthetic peptides with the sequence of transmembrane helices 5 and 6 of CB1R, fused to a cell-penetrating peptide, were able to disrupt receptor heteromerization in vivo, leading to a selective abrogation of memory impairments caused by exposure to THC. These data reveal a novel molecular mechanism for the functional interaction between CB1R and 5-HT2AR mediating cognitive impairment. CB1R-5-HT2AR heteromers are thus good targets to dissociate the cognitive deficits induced by THC from its beneficial antinociceptive properties.", "link"=>"http://www.mendeley.com/research/cognitive-impairment-induced-delta9tetrahydrocannabinol-occurs-through-heteromers-between-cannabinoi-2", "reader_count"=>136, "reader_count_by_academic_status"=>{"Unspecified"=>6, "Professor > Associate Professor"=>3, "Student > Doctoral Student"=>10, "Researcher"=>25, "Student > Ph. D. Student"=>30, "Student > Postgraduate"=>5, "Other"=>8, "Student > Master"=>23, "Student > Bachelor"=>20, "Professor"=>6}, "reader_count_by_user_role"=>{"Unspecified"=>6, "Professor > Associate Professor"=>3, "Student > Doctoral Student"=>10, "Researcher"=>25, "Student > Ph. D. Student"=>30, "Student > Postgraduate"=>5, "Other"=>8, "Student > Master"=>23, "Student > Bachelor"=>20, "Professor"=>6}, "reader_count_by_subject_area"=>{"Unspecified"=>12, "Engineering"=>3, "Biochemistry, Genetics and Molecular Biology"=>13, "Materials Science"=>1, "Medicine and Dentistry"=>15, "Agricultural and Biological Sciences"=>44, "Neuroscience"=>21, "Pharmacology, Toxicology and Pharmaceutical Science"=>9, "Psychology"=>4, "Chemistry"=>10, "Social Sciences"=>2, "Computer Science"=>2}, "reader_count_by_subdiscipline"=>{"Engineering"=>{"Engineering"=>3}, "Materials Science"=>{"Materials Science"=>1}, "Medicine and Dentistry"=>{"Medicine and Dentistry"=>15}, "Neuroscience"=>{"Neuroscience"=>21}, "Chemistry"=>{"Chemistry"=>10}, "Social Sciences"=>{"Social Sciences"=>2}, "Psychology"=>{"Psychology"=>4}, "Agricultural and Biological Sciences"=>{"Agricultural and Biological Sciences"=>44}, "Computer Science"=>{"Computer Science"=>2}, "Biochemistry, Genetics and Molecular Biology"=>{"Biochemistry, Genetics and Molecular Biology"=>13}, "Unspecified"=>{"Unspecified"=>12}, "Pharmacology, Toxicology and Pharmaceutical Science"=>{"Pharmacology, Toxicology and Pharmaceutical Science"=>9}}, "reader_count_by_country"=>{"Canada"=>1, "Colombia"=>1, "United States"=>3, "Uruguay"=>1, "Italy"=>1, "France"=>1, "Portugal"=>1, "Spain"=>3}, "group_count"=>4}

CrossRef

Scopus | Further Information

{"@_fa"=>"true", "link"=>[{"@_fa"=>"true", "@ref"=>"self", "@href"=>"https://api.elsevier.com/content/abstract/scopus_id/84938703167"}, {"@_fa"=>"true", "@ref"=>"author-affiliation", "@href"=>"https://api.elsevier.com/content/abstract/scopus_id/84938703167?field=author,affiliation"}, {"@_fa"=>"true", "@ref"=>"scopus", "@href"=>"https://www.scopus.com/inward/record.uri?partnerID=HzOxMe3b&scp=84938703167&origin=inward"}, {"@_fa"=>"true", "@ref"=>"scopus-citedby", "@href"=>"https://www.scopus.com/inward/citedby.uri?partnerID=HzOxMe3b&scp=84938703167&origin=inward"}], "prism:url"=>"https://api.elsevier.com/content/abstract/scopus_id/84938703167", "dc:identifier"=>"SCOPUS_ID:84938703167", "eid"=>"2-s2.0-84938703167", "dc:title"=>"Cognitive impairment induced by delta9- tetrahydrocannabinol occurs through heteromers between cannabinoid CB<inf>1</inf> and serotonin 5-HT<inf>2A</inf> receptors", "dc:creator"=>"Viñals X.", "prism:publicationName"=>"PLoS Biology", "prism:issn"=>"15449173", "prism:eIssn"=>"15457885", "prism:volume"=>"13", "prism:issueIdentifier"=>"7", "prism:pageRange"=>nil, "prism:coverDate"=>"2015-01-01", "prism:coverDisplayDate"=>"2015", "prism:doi"=>"10.1371/journal.pbio.1002194", "citedby-count"=>"82", "affiliation"=>[{"@_fa"=>"true", "affilname"=>"Universitat Pompeu Fabra Barcelona", "affiliation-city"=>"Barcelona", "affiliation-country"=>"Spain"}], "pubmed-id"=>"26158621", "prism:aggregationType"=>"Journal", "subtype"=>"ar", "subtypeDescription"=>"Article", "source-id"=>"12977", "openaccess"=>"1", "openaccessFlag"=>true}

Article Coverage

Article Coverage Curated

Facebook

  • {"url"=>"http%3A%2F%2Fjournals.plos.org%2Fplosbiology%2Farticle%3Fid%3D10.1371%252Fjournal.pbio.1002194", "share_count"=>234, "like_count"=>559, "comment_count"=>153, "click_count"=>0, "total_count"=>946}

Journal Comments | Further Information

Twitter

Counter

  • {"month"=>"7", "year"=>"2015", "pdf_views"=>"781", "xml_views"=>"9", "html_views"=>"10819"}
  • {"month"=>"8", "year"=>"2015", "pdf_views"=>"253", "xml_views"=>"8", "html_views"=>"2683"}
  • {"month"=>"9", "year"=>"2015", "pdf_views"=>"96", "xml_views"=>"0", "html_views"=>"772"}
  • {"month"=>"10", "year"=>"2015", "pdf_views"=>"68", "xml_views"=>"0", "html_views"=>"537"}
  • {"month"=>"11", "year"=>"2015", "pdf_views"=>"35", "xml_views"=>"0", "html_views"=>"410"}
  • {"month"=>"12", "year"=>"2015", "pdf_views"=>"20", "xml_views"=>"0", "html_views"=>"263"}
  • {"month"=>"1", "year"=>"2016", "pdf_views"=>"39", "xml_views"=>"0", "html_views"=>"353"}
  • {"month"=>"2", "year"=>"2016", "pdf_views"=>"34", "xml_views"=>"0", "html_views"=>"693"}
  • {"month"=>"3", "year"=>"2016", "pdf_views"=>"28", "xml_views"=>"0", "html_views"=>"212"}
  • {"month"=>"4", "year"=>"2016", "pdf_views"=>"29", "xml_views"=>"0", "html_views"=>"264"}
  • {"month"=>"5", "year"=>"2016", "pdf_views"=>"28", "xml_views"=>"0", "html_views"=>"241"}
  • {"month"=>"6", "year"=>"2016", "pdf_views"=>"25", "xml_views"=>"0", "html_views"=>"154"}
  • {"month"=>"7", "year"=>"2016", "pdf_views"=>"24", "xml_views"=>"0", "html_views"=>"133"}
  • {"month"=>"8", "year"=>"2016", "pdf_views"=>"37", "xml_views"=>"0", "html_views"=>"155"}
  • {"month"=>"9", "year"=>"2016", "pdf_views"=>"35", "xml_views"=>"0", "html_views"=>"276"}
  • {"month"=>"10", "year"=>"2016", "pdf_views"=>"24", "xml_views"=>"0", "html_views"=>"298"}
  • {"month"=>"11", "year"=>"2016", "pdf_views"=>"13", "xml_views"=>"0", "html_views"=>"175"}
  • {"month"=>"12", "year"=>"2016", "pdf_views"=>"25", "xml_views"=>"1", "html_views"=>"151"}
  • {"month"=>"1", "year"=>"2017", "pdf_views"=>"19", "xml_views"=>"1", "html_views"=>"205"}
  • {"month"=>"2", "year"=>"2017", "pdf_views"=>"27", "xml_views"=>"0", "html_views"=>"182"}
  • {"month"=>"3", "year"=>"2017", "pdf_views"=>"79", "xml_views"=>"1", "html_views"=>"210"}
  • {"month"=>"4", "year"=>"2017", "pdf_views"=>"25", "xml_views"=>"1", "html_views"=>"181"}
  • {"month"=>"5", "year"=>"2017", "pdf_views"=>"45", "xml_views"=>"4", "html_views"=>"230"}
  • {"month"=>"6", "year"=>"2017", "pdf_views"=>"21", "xml_views"=>"3", "html_views"=>"256"}
  • {"month"=>"7", "year"=>"2017", "pdf_views"=>"22", "xml_views"=>"5", "html_views"=>"129"}
  • {"month"=>"8", "year"=>"2017", "pdf_views"=>"11", "xml_views"=>"4", "html_views"=>"72"}
  • {"month"=>"9", "year"=>"2017", "pdf_views"=>"21", "xml_views"=>"4", "html_views"=>"92"}
  • {"month"=>"10", "year"=>"2017", "pdf_views"=>"28", "xml_views"=>"1", "html_views"=>"138"}
  • {"month"=>"11", "year"=>"2017", "pdf_views"=>"27", "xml_views"=>"0", "html_views"=>"169"}
  • {"month"=>"12", "year"=>"2017", "pdf_views"=>"27", "xml_views"=>"1", "html_views"=>"123"}
  • {"month"=>"1", "year"=>"2018", "pdf_views"=>"20", "xml_views"=>"0", "html_views"=>"65"}
  • {"month"=>"2", "year"=>"2018", "pdf_views"=>"59", "xml_views"=>"0", "html_views"=>"53"}
  • {"month"=>"3", "year"=>"2018", "pdf_views"=>"19", "xml_views"=>"0", "html_views"=>"55"}
  • {"month"=>"4", "year"=>"2018", "pdf_views"=>"25", "xml_views"=>"0", "html_views"=>"55"}
  • {"month"=>"5", "year"=>"2018", "pdf_views"=>"39", "xml_views"=>"10", "html_views"=>"96"}
  • {"month"=>"6", "year"=>"2018", "pdf_views"=>"24", "xml_views"=>"7", "html_views"=>"26"}
  • {"month"=>"7", "year"=>"2018", "pdf_views"=>"23", "xml_views"=>"10", "html_views"=>"37"}
  • {"month"=>"8", "year"=>"2018", "pdf_views"=>"39", "xml_views"=>"2", "html_views"=>"56"}
  • {"month"=>"9", "year"=>"2018", "pdf_views"=>"28", "xml_views"=>"2", "html_views"=>"48"}
  • {"month"=>"10", "year"=>"2018", "pdf_views"=>"29", "xml_views"=>"7", "html_views"=>"64"}
  • {"month"=>"11", "year"=>"2018", "pdf_views"=>"73", "xml_views"=>"0", "html_views"=>"59"}
  • {"month"=>"12", "year"=>"2018", "pdf_views"=>"26", "xml_views"=>"4", "html_views"=>"21"}
  • {"month"=>"1", "year"=>"2019", "pdf_views"=>"46", "xml_views"=>"1", "html_views"=>"73"}
  • {"month"=>"2", "year"=>"2019", "pdf_views"=>"58", "xml_views"=>"0", "html_views"=>"48"}
  • {"month"=>"3", "year"=>"2019", "pdf_views"=>"70", "xml_views"=>"2", "html_views"=>"82"}
  • {"month"=>"4", "year"=>"2019", "pdf_views"=>"54", "xml_views"=>"2", "html_views"=>"83"}
  • {"month"=>"5", "year"=>"2019", "pdf_views"=>"57", "xml_views"=>"4", "html_views"=>"75"}
  • {"month"=>"6", "year"=>"2019", "pdf_views"=>"28", "xml_views"=>"1", "html_views"=>"35"}
  • {"month"=>"7", "year"=>"2019", "pdf_views"=>"48", "xml_views"=>"0", "html_views"=>"45"}
  • {"month"=>"8", "year"=>"2019", "pdf_views"=>"35", "xml_views"=>"0", "html_views"=>"46"}
  • {"month"=>"9", "year"=>"2019", "pdf_views"=>"67", "xml_views"=>"0", "html_views"=>"53"}
  • {"month"=>"10", "year"=>"2019", "pdf_views"=>"58", "xml_views"=>"1", "html_views"=>"60"}
  • {"month"=>"11", "year"=>"2019", "pdf_views"=>"41", "xml_views"=>"0", "html_views"=>"48"}
  • {"month"=>"12", "year"=>"2019", "pdf_views"=>"47", "xml_views"=>"0", "html_views"=>"89"}
  • {"month"=>"1", "year"=>"2020", "pdf_views"=>"45", "xml_views"=>"0", "html_views"=>"66"}
  • {"month"=>"2", "year"=>"2020", "pdf_views"=>"22", "xml_views"=>"1", "html_views"=>"40"}
  • {"month"=>"3", "year"=>"2020", "pdf_views"=>"9", "xml_views"=>"3", "html_views"=>"53"}
  • {"month"=>"4", "year"=>"2020", "pdf_views"=>"42", "xml_views"=>"0", "html_views"=>"46"}
  • {"month"=>"5", "year"=>"2020", "pdf_views"=>"51", "xml_views"=>"1", "html_views"=>"53"}
  • {"month"=>"6", "year"=>"2020", "pdf_views"=>"23", "xml_views"=>"1", "html_views"=>"39"}
  • {"month"=>"7", "year"=>"2020", "pdf_views"=>"20", "xml_views"=>"0", "html_views"=>"49"}
  • {"month"=>"8", "year"=>"2020", "pdf_views"=>"21", "xml_views"=>"1", "html_views"=>"50"}
  • {"month"=>"9", "year"=>"2020", "pdf_views"=>"26", "xml_views"=>"0", "html_views"=>"34"}
  • {"month"=>"10", "year"=>"2020", "pdf_views"=>"26", "xml_views"=>"0", "html_views"=>"72"}
  • {"month"=>"11", "year"=>"2020", "pdf_views"=>"19", "xml_views"=>"3", "html_views"=>"27"}

Figshare

  • {"files"=>["https://ndownloader.figshare.com/files/2169479"], "description"=>"<p>(A) The administration of THC (3 and 10 mg/kg) induced memory impairments in the novel object recognition test in WT mice as compared to vehicle (VEH) treatment (<i>n</i> = 8–11), and this effect was significantly abrogated in 5-HT<sub>2A</sub>R KO mice at the dose of 3 mg/kg, but not at the dose of 10 mg/kg. (B) The anxiolytic effects of THC (0.3 mg/kg) observed in WT mice tested in the elevated plus maze were blocked in 5-HT<sub>2A</sub>R KO mice (<i>n</i> = 9–12). (C) The increase in social interaction induced by THC (0.3 mg/kg) in WT mice was abolished in 5-HT<sub>2A</sub>R KO mice (<i>n</i> = 5–7). (D) Neuronal firing of representative dorsal raphe (DR) neurons before and after THC administration (1 and 10 nM) in WT (upper panel) and 5-HT<sub>2A</sub>R KO (lower panel) animals. (E) A challenge with THC (1 nM) reduced the percent change in firing rate of DR neurons from WT mice, and this effect was blunted in DR neurons from 5-HT<sub>2A</sub>R KO mice. No significant differences between genotypes were observed following a challenge with THC at 10 nM (<i>n</i> = 7–14). (F) The basal firing rate of DR neurons was similar in WT and 5-HT<sub>2A</sub>R KO animals (<i>n</i> = 20–24). (G–I) Withdrawal symptoms, including paw tremor (G), sniffing (H), and global withdrawal score (GWS) (I), were reduced in 5-HT<sub>2A</sub>R KO mice when compared to WT mice. Data are mean + standard error of the mean (SEM). * <i>p</i> < 0.05, ** <i>p</i> < 0.01, and *** <i>p</i> < 0.001 versus VEH; # <i>p</i> < 0.05 versus WT mice. The statistical analyses used and their corresponding F and <i>p</i>-values are shown in <a href=\"http://www.plosbiology.org/article/info:doi/10.1371/journal.pbio.1002194#pbio.1002194.s013\" target=\"_blank\">S1 Table</a>.</p>", "links"=>[], "tags"=>["CB 1R", "cannabinoid CB 1 receptors", "Cannabinoid CB 1", "transmembrane helices 5", "2a", "thc", "ht", "2AR", "impairment", "CB 1R heteromers", "Cognitive Impairment Induced", "antinociceptive effects"], "article_id"=>1478518, "categories"=>["Biological Sciences"], "users"=>["Xavier Viñals", "Estefanía Moreno", "Laurence Lanfumey", "Arnau Cordomí", "Antoni Pastor", "Rafael de la Torre", "Paola Gasperini", "Gemma Navarro", "Lesley A. Howell", "Leonardo Pardo", "Carmen Lluís", "Enric I. Canela", "Peter J. McCormick", "Rafael Maldonado", "Patricia Robledo"], "doi"=>["https://dx.doi.org/10.1371/journal.pbio.1002194.g001"], "stats"=>{"downloads"=>0, "page_views"=>0, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_5_HT_2A_R_mediates_THC_induced_amnesic_and_anxiolytic_like_effects_/1478518", "title"=>"5-HT<sub>2A</sub>R mediates THC-induced amnesic- and anxiolytic-like effects.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2015-07-09 03:25:07"}
  • {"files"=>["https://ndownloader.figshare.com/files/2169483"], "description"=>"<p>(A) Locomotor activity (% of baseline) was dose-dependently reduced in both WT and 5-HT<sub>2A</sub>R KO mice treated with THC (0.3, 1, 3, and 10 mg/kg) as compared to vehicle (VEH) administration (<i>n</i> = 5–15). (B) THC induced hypothermia at the dose of 10 mg/kg to a similar extent in WT and 5-HT<sub>2A</sub>R KO mice (<i>n</i> = 13–24). (C) In the tail-immersion test, percent analgesia was dose-dependently increased by THC (1, 3, and 10 mg/kg) in both WT and 5-HT<sub>2A</sub>R KO mice (<i>n</i> = 10–16). In the hot-plate test, the percent of analgesia as calculated from the latency to paw-licking (D) and to jumping behavior (E) was similar in WT and KO animals treated with THC (1, 3, and 10 mg/kg) as compared to VEH administration (<i>n</i> = 7–16). (F) No significant differences between genotypes were observed in anxiogenic-like behavior induced by THC (3 mg/kg) (<i>n</i> = 6–10). (G) Both WT and 5-HT<sub>2A</sub>R KO mice acquired WIN 55,212–2 self-administration behavior and responded equally for this drug during the 12 d of training (<i>n</i> = 12–15). Data are mean + SEM. * <i>p</i> < 0.05, ** <i>p</i> < 0.01, and *** <i>p</i> < 0.001 versus VEH-treated animals. The statistical analyses used and their corresponding F and <i>p</i>-values are shown in <a href=\"http://www.plosbiology.org/article/info:doi/10.1371/journal.pbio.1002194#pbio.1002194.s013\" target=\"_blank\">S1 Table</a>.</p>", "links"=>[], "tags"=>["CB 1R", "cannabinoid CB 1 receptors", "Cannabinoid CB 1", "transmembrane helices 5", "2a", "thc", "ht", "2AR", "impairment", "CB 1R heteromers", "Cognitive Impairment Induced", "antinociceptive effects"], "article_id"=>1478522, "categories"=>["Biological Sciences"], "users"=>["Xavier Viñals", "Estefanía Moreno", "Laurence Lanfumey", "Arnau Cordomí", "Antoni Pastor", "Rafael de la Torre", "Paola Gasperini", "Gemma Navarro", "Lesley A. Howell", "Leonardo Pardo", "Carmen Lluís", "Enric I. Canela", "Peter J. McCormick", "Rafael Maldonado", "Patricia Robledo"], "doi"=>["https://dx.doi.org/10.1371/journal.pbio.1002194.g002"], "stats"=>{"downloads"=>0, "page_views"=>0, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_5_HT_2A_R_does_not_mediate_THC_induced_hypolocomotion_hypothermia_analgesia_anxiogenic_like_behavior_or_the_reinforcing_properties_of_WIN_55_212_8211_2_/1478522", "title"=>"5-HT<sub>2A</sub>R does not mediate THC-induced hypolocomotion, hypothermia, analgesia, anxiogenic-like behavior, or the reinforcing properties of WIN 55,212–2.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2015-07-09 03:25:07"}
  • {"files"=>["https://ndownloader.figshare.com/files/2169487"], "description"=>"<p>In (A and B), the DMR analysis was performed. In (A), cells were pretreated overnight with medium (black line), with 10 ng/ml pertussis toxin (purple line), or with 100 ng/ml cholera toxin (yellow line) and were stimulated with 100 nM DOI. Alternatively, cells pretreated overnight with medium (red line), with 10 ng/ml pertussis toxin (green line), or with 100 ng/ml cholera toxin (blue line) were stimulated with 50 nM WIN 55,212–2. In (B), cells were pretreated 30 min with medium (black line) or with 1 μM of the Gq protein inhibitor YM-254890 (orange line) and were stimulated with 100 nM DOI. In all cases, the resulting picometer shifts of reflected light wavelength (pm) were monitored over time. Each curve is the mean of a representative optical trace experiment carried out in triplicates. In (C), intracellular calcium release was monitored in cells expressing CB<sub>1</sub>R and 5-HT<sub>2A</sub>R receptors treated with 100 nM DOI (black curve) or with 50 nM WIN 55,212–2 (red curve). Values are mean ± SEM of <i>n</i> = 3. In (D), cAMP production was determined in cells treated with medium (control), treated overnight with 10 ng/ml pertussis toxin (PTX), or treated 1 h with 100 ng/ml cholera toxin (CTX). Cells were stimulated with 100 nM DOI or 100 nM WIN 55,212–2 (WIN) in the absence or in the presence of 0.5 μM forskolin (FK). Values (cAMP produced in each condition minus basal stimulation in the absence of forskolin or agonists) represent mean ± SEM of <i>n</i> = 3–4 and are expressed as the percentage of the forskolin-treated cells in each conditions (120–150 pmols cAMP/10<sup>6</sup> cells). One-way ANOVA followed by a Dunnett’s multiple comparison test showed a significant effect over the forskolin-alone effect in each condition (* <i>p</i> < 0.05, ** <i>p</i> < 0.01).</p>", "links"=>[], "tags"=>["CB 1R", "cannabinoid CB 1 receptors", "Cannabinoid CB 1", "transmembrane helices 5", "2a", "thc", "ht", "2AR", "impairment", "CB 1R heteromers", "Cognitive Impairment Induced", "antinociceptive effects"], "article_id"=>1478524, "categories"=>["Biological Sciences"], "users"=>["Xavier Viñals", "Estefanía Moreno", "Laurence Lanfumey", "Arnau Cordomí", "Antoni Pastor", "Rafael de la Torre", "Paola Gasperini", "Gemma Navarro", "Lesley A. Howell", "Leonardo Pardo", "Carmen Lluís", "Enric I. Canela", "Peter J. McCormick", "Rafael Maldonado", "Patricia Robledo"], "doi"=>["https://dx.doi.org/10.1371/journal.pbio.1002194.g003"], "stats"=>{"downloads"=>0, "page_views"=>0, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_CB_1_R_and_5_HT_2A_R_are_associated_to_Gi_signaling_when_coexpressed_HEK_293Tcells_expressing_CB_1_R_and_5_HT_2A_R_receptors_were_used_/1478524", "title"=>"CB<sub>1</sub>R and 5-HT<sub>2A</sub>R are associated to Gi signaling when coexpressed. HEK-293Tcells expressing CB<sub>1</sub>R and 5-HT<sub>2A</sub>R receptors were used.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2015-07-09 03:25:07"}
  • {"files"=>["https://ndownloader.figshare.com/files/2169491"], "description"=>"<p>In (A), BRET saturation experiments were performed in HEK-293T cells transfected with 0.025 μg of 5-HT<sub>2A</sub>R-Rluc cDNA and increasing amounts of CB<sub>1</sub>R-YFP cDNA (0.05 μg to 1.5 μg, black curve), with 0.5 μg of dopamine D<sub>1</sub>R-Rluc cDNA and increasing amounts of CB<sub>1</sub>R-YFP cDNA (0.5 μg to 6 μg, yellow line), or with 0.025 μg of 5-HT<sub>2A</sub>R-Rluc cDNA and increasing amounts of adenosine A<sub>1</sub>R-YFP cDNA (0.05 μg to 1.5 μg, red line). The relative amount of BRET is given as a function of 100 x the ratio between the fluorescence of the acceptor (YFP) and the luciferase activity of the donor (Rluc). BRET is expressed as milli BRET units (mBU) and is given as the mean ± standard deviation (SD) of 3–6 experiments grouped as a function of the amount of BRET acceptor. In (B), a schematic representation of fluorescence complementation experiments is depicted in the left panel showing that fluorescence only appears after the YFP Venus hemiprotein complementation due to the proximity of two receptors fused to hemi-YFP Venus proteins (cYFP or nYFP). In the right panel, fluorescence at 530 nm was detected in HEK-293T cells transfected with different amounts of cDNA corresponding to both 5-HT<sub>2A</sub>R-cYFP and CB<sub>1</sub>R-nYFP (equal amount for each construct), but not in negative controls in which cells were transfected with cDNA corresponding to 5-HT<sub>2A</sub>R-cYFP and the noninteracting adenosine A<sub>1</sub> receptor-nYFP or CB<sub>1</sub>R-nYFP and the noninteracting dopamine D<sub>1</sub> receptor-cYFP. One-way ANOVA followed by a Dunnett’s multiple comparison test showed a significant fluorescence over basal values in HEK-293T cells (** <i>p</i> < 0.01, *** <i>p</i> < 0.001). In (C), PLAs were performed in HEK-293T cells expressing CB<sub>1</sub>R and 5-HT<sub>2A</sub>R. Confocal microscopy images (superimposed sections) are shown in which heteromers appear as green spots. In all cases, cell nuclei were stained with DAPI (blue). Scale bars = 20 μm. In (D), PLAs were performed in nontransfected HEK-293T cells, cells transiently transfected with 0.5 μg of CB<sub>1</sub>R or 5-HT<sub>2A</sub>R cDNA (negative controls, white columns), or with increasing amounts of CB<sub>1</sub>R and 5-HT<sub>2A</sub>R cDNA (black columns). In each case, the ratio between the number of green spots and the number of cells showing spots (ratio r) was calculated. One-way ANOVA followed by a Dunnett’s multiple comparison test showed a significant PLA staining over nontranfected cells (*** <i>p</i> < 0.001).</p>", "links"=>[], "tags"=>["CB 1R", "cannabinoid CB 1 receptors", "Cannabinoid CB 1", "transmembrane helices 5", "2a", "thc", "ht", "2AR", "impairment", "CB 1R heteromers", "Cognitive Impairment Induced", "antinociceptive effects"], "article_id"=>1478528, "categories"=>["Biological Sciences"], "users"=>["Xavier Viñals", "Estefanía Moreno", "Laurence Lanfumey", "Arnau Cordomí", "Antoni Pastor", "Rafael de la Torre", "Paola Gasperini", "Gemma Navarro", "Lesley A. Howell", "Leonardo Pardo", "Carmen Lluís", "Enric I. Canela", "Peter J. McCormick", "Rafael Maldonado", "Patricia Robledo"], "doi"=>["https://dx.doi.org/10.1371/journal.pbio.1002194.g004"], "stats"=>{"downloads"=>0, "page_views"=>0, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_5_HT_2A_R_and_CB_1_R_form_heteromers_in_transfected_cells_/1478528", "title"=>"5-HT<sub>2A</sub>R and CB<sub>1</sub>R form heteromers in transfected cells.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2015-07-09 03:25:07"}
  • {"files"=>["https://ndownloader.figshare.com/files/2169494"], "description"=>"<p>In (A and E), cAMP production was determined in HEK-293Tcells expressing CB<sub>1</sub>R and 5-HT<sub>2A</sub>R after stimulation with 100 nM DOI, 100 nM WIN 55,212–2 (WIN), or both in the absence or in the presence of 0.5 μM forskolin. In (E), cells were first preincubated either with the CB<sub>1</sub>R antagonist rimonabant (1 μM, RIM) or the 5-HT<sub>2A</sub>R antagonist MDL 100,907 (300 nM) for 20 min prior to being stimulated. Values (cAMP produced in each condition minus basal stimulation in the absence of forskolin or agonists) represent mean ± SEM of <i>n</i> = 3–4 and are expressed as the percentage of the forskolin-treated cells in each condition (120–150 pmols cAMP/10<sup>6</sup> cells). One-way ANOVA followed by a Bonferroni post hoc tests showed a significant effect over the forskolin-alone effect in each condition (** <i>p</i> < 0.01, *** <i>p</i> <0.001) or of the antagonist plus agonist treatment over the agonist treatment (# <i>p</i> < 0.05, ## <i>p</i> < 0.01, ### <i>p</i> < 0.001). In (B and F), β arrestin II recruitment was measured by BRET experiments in cells transfected with 2 μg of CB<sub>1</sub>R cDNA, 0.2 μg of β-arrestin II-Rluc cDNA, and 1 μg of 5-H<sub>2A</sub>R-YFP cDNA. Cells were not preincubated with antagonist (B) or were preincubated (F) for 20 min with vehicle, rimonabant (1 μM, RIM), or MDL 100,907 (300 nM, MDL). Cells were not treated (BRET < 10) or were treated for 7 min with WIN 55,212–2 (100 nM, WIN) or DOI (100 nM) before BRET determination. Values represent mean ± SEM of <i>n</i> = 4–6. One-way ANOVA followed by a Bonferroni post hoc tests showed a significant effect over not-treated cells (* <i>p</i> < 0.05, ** <i>p</i> < 0.01, *** <i>p</i> <0.001) or of the antagonist plus agonist treatment over the agonist treatment (## <i>p</i> < 0.01, ### <i>p</i> < 0.001). In (C, D, G, and H), cells expressing CB<sub>1</sub>R and 5-HT<sub>2A</sub>R were not preincubated with antagonist (C and D) or were preincubated for 15 min with rimonabant (1 μM, RIM) or MDL 100,907 (300 nM, MDL) (G and H) and stimulated for 5 min with WIN 55,212–2 (100 nM,WIN) or DOI (100 nM). Quantification of phosphorylated ERK 1/2 (C and G) or Akt (D and H) was determined by western blot. Values, expressed as percentage of basal (nontreated cells), were mean ± SEM of <i>n</i> = 3–10. One-way ANOVA followed by a Bonferroni post hoc tests showed a significant effect over basal (* <i>p</i> < 0.05, ** <i>p</i> < 0.01, ** <i>p</i> < 0.001) or of the antagonist plus agonist treatment over the agonist treatment (# <i>p</i> < 0.05, ## <i>p</i> < 0.01, ### <i>p</i> < 0.001).</p>", "links"=>[], "tags"=>["CB 1R", "cannabinoid CB 1 receptors", "Cannabinoid CB 1", "transmembrane helices 5", "2a", "thc", "ht", "2AR", "impairment", "CB 1R heteromers", "Cognitive Impairment Induced", "antinociceptive effects"], "article_id"=>1478531, "categories"=>["Biological Sciences"], "users"=>["Xavier Viñals", "Estefanía Moreno", "Laurence Lanfumey", "Arnau Cordomí", "Antoni Pastor", "Rafael de la Torre", "Paola Gasperini", "Gemma Navarro", "Lesley A. Howell", "Leonardo Pardo", "Carmen Lluís", "Enric I. Canela", "Peter J. McCormick", "Rafael Maldonado", "Patricia Robledo"], "doi"=>["https://dx.doi.org/10.1371/journal.pbio.1002194.g005"], "stats"=>{"downloads"=>0, "page_views"=>0, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_A_profile_of_CB_1_R_5_HT_2A_R_heteromer_signaling_/1478531", "title"=>"A profile of CB<sub>1</sub>R-5-HT<sub>2A</sub>R heteromer signaling.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2015-07-09 03:25:07"}
  • {"files"=>["https://ndownloader.figshare.com/files/2169495"], "description"=>"<p>In (A), agonist binding to CB<sub>1</sub>R (blue) or 5-HT<sub>2A</sub>R (light green) triggers the conformational changes of TMs 5 and 6, opening the intracellular cavity for Gi and Gq binding, respectively. In (B), the formation of the CB<sub>1</sub>R-5-HT<sub>2A</sub>R heteromer makes both receptors signal via Gi. In (C), rimonabant binding to CB<sub>1</sub>R or MDL 100,907 to 5-HT<sub>2A</sub>R stabilizes the closed conformation of the receptor, facilitating heterodimerization via TMs 5 and 6 as in the crystal structure of the μ-opioid receptor. In this assembly, both protomers are locked in the closed conformation since the opening of TMs 5 and 6 for G-protein binding is not feasible (see <a href=\"http://www.plosbiology.org/article/info:doi/10.1371/journal.pbio.1002194#pbio.1002194.s008\" target=\"_blank\">S7 Fig</a>). Bidirectional cross antagonism is due to the fact that antagonist binding to any protomer must, in addition to its common role in a monomeric signaling unit, disrupt this very stable four-helix association. (D) In agreement, bidirectional cross antagonism is abrogated following treatment with TM 5 or TM 6 interference peptides (dark blue), which disrupt the heteromer structure.</p>", "links"=>[], "tags"=>["CB 1R", "cannabinoid CB 1 receptors", "Cannabinoid CB 1", "transmembrane helices 5", "2a", "thc", "ht", "2AR", "impairment", "CB 1R heteromers", "Cognitive Impairment Induced", "antinociceptive effects"], "article_id"=>1478532, "categories"=>["Biological Sciences"], "users"=>["Xavier Viñals", "Estefanía Moreno", "Laurence Lanfumey", "Arnau Cordomí", "Antoni Pastor", "Rafael de la Torre", "Paola Gasperini", "Gemma Navarro", "Lesley A. Howell", "Leonardo Pardo", "Carmen Lluís", "Enric I. Canela", "Peter J. McCormick", "Rafael Maldonado", "Patricia Robledo"], "doi"=>["https://dx.doi.org/10.1371/journal.pbio.1002194.g006"], "stats"=>{"downloads"=>0, "page_views"=>0, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Proposed_functional_properties_of_CB_1_R_5_HT_2A_R_heteromers_/1478532", "title"=>"Proposed functional properties of CB<sub>1</sub>R-5-HT<sub>2A</sub>R heteromers.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2015-07-09 03:25:07"}
  • {"files"=>["https://ndownloader.figshare.com/files/2169503"], "description"=>"<p>In (A), HEK-293T cells expressing CB<sub>1</sub>R and 5-HT<sub>2A</sub>R were treated for 4 h with vehicle (left panel) or 4 μM of CB<sub>1</sub>R TM 7, TM 5, or TM 6 interference peptides before performing proximity ligation assays. Confocal microscopy images (superimposed sections) are shown in which heteromers appear as green spots in cells treated with vehicle and with TM 7 interference peptide, but not in cells treated with TM 5 or TM 6 interference peptides. In all cases, cell nuclei were stained with DAPI (blue). Scale bars = 20 μm. In (B–D), HEK-293T cells expressing CB<sub>1</sub>R and 5-HT<sub>2A</sub>R were preincubated for 20 min with rimonabant (1 μM, RIM) or MDL 100,907 (300 nM, MDL) before stimulation for 10 min (B) or 5 min (C, D) with the CB<sub>1</sub>R agonist WIN 55,212–2 (100 nM), the 5-HT<sub>2A</sub>R agonist DOI (100 nM), or both in the presence (B) or absence (C, D) of 0.5 μM forskolin. In (B), cAMP production was determined. Values represent mean ± SEM of <i>n</i> = 3–9 and are expressed as the percentage of the cAMP produced in forskolin-treated cells. Quantification of phosphorylated ERK 1/2 (C) or Akt (D) was determined by western blot. Values, expressed as a percentage of basal (nontreated cells), were mean ± SEM of <i>n</i> = 3–6. One-way ANOVA followed by a Bonferroni post hoc tests showed a significant effect over forskolin’s effects alone in each condition (B) or over basal (C, D) (* <i>p</i> < 0.05, ** <i>p</i> < 0.01, *** <i>p</i> <0.001) or of the antagonist plus agonist treatment over the agonist treatment (# <i>p</i> < 0.05, ## <i>p</i> < 0.01, ### <i>p</i> < 0.001).</p>", "links"=>[], "tags"=>["CB 1R", "cannabinoid CB 1 receptors", "Cannabinoid CB 1", "transmembrane helices 5", "2a", "thc", "ht", "2AR", "impairment", "CB 1R heteromers", "Cognitive Impairment Induced", "antinociceptive effects"], "article_id"=>1478534, "categories"=>["Biological Sciences"], "users"=>["Xavier Viñals", "Estefanía Moreno", "Laurence Lanfumey", "Arnau Cordomí", "Antoni Pastor", "Rafael de la Torre", "Paola Gasperini", "Gemma Navarro", "Lesley A. Howell", "Leonardo Pardo", "Carmen Lluís", "Enric I. Canela", "Peter J. McCormick", "Rafael Maldonado", "Patricia Robledo"], "doi"=>["https://dx.doi.org/10.1371/journal.pbio.1002194.g007"], "stats"=>{"downloads"=>0, "page_views"=>0, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Interacting_protomer_domains_in_CB_1_R_5_HT_2A_R_heteromers_and_heteromer_disruption_by_TM_interference_peptides_/1478534", "title"=>"Interacting protomer domains in CB<sub>1</sub>R-5-HT<sub>2A</sub>R heteromers and heteromer disruption by TM interference peptides.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2015-07-09 03:25:07"}
  • {"files"=>["https://ndownloader.figshare.com/files/2169519"], "description"=>"<p>In (A), PLAs were performed using slices of mouse hippocampus CA3, caudate-putamen (striatum), cortex (somatomotor layers 1, 2, and 3) or nucleus accumbens (NaC). Confocal microscopy images (superimposed sections) are shown in which heteromers appear as green spots in WT mice, but not in 5-HT<sub>2A</sub>R KO or CB<sub>1</sub>R KO mice in the hippocampus, caudate-putamen, and cortex. Any staining was observed in the nucleus accumbens of either WT or KO animals. In all cases, cell nuclei were stained with DAPI (blue). Scale bars = 20 μm. In (B), the number of cells containing one or more green spots is expressed as the percentage of the total number of cells (blue nucleus) in the hippocampus, striatum, cortex, and nucleus accumbens of WT (white bars), 5-HT<sub>2A</sub>R KO (black bars), or CB<sub>1</sub>R KO (grey bars) mice. Data (percentage of positive cells) are the mean ± SEM of counts in 4–9 different fields (see experimental procedures). Student’s <i>t</i> test showed a significant effect over 5-HT<sub>2A</sub>R KO or over CB<sub>1</sub>R KO mice in each condition (*** <i>p</i> < 0.001).</p>", "links"=>[], "tags"=>["CB 1R", "cannabinoid CB 1 receptors", "Cannabinoid CB 1", "transmembrane helices 5", "2a", "thc", "ht", "2AR", "impairment", "CB 1R heteromers", "Cognitive Impairment Induced", "antinociceptive effects"], "article_id"=>1478550, "categories"=>["Biological Sciences"], "users"=>["Xavier Viñals", "Estefanía Moreno", "Laurence Lanfumey", "Arnau Cordomí", "Antoni Pastor", "Rafael de la Torre", "Paola Gasperini", "Gemma Navarro", "Lesley A. Howell", "Leonardo Pardo", "Carmen Lluís", "Enric I. Canela", "Peter J. McCormick", "Rafael Maldonado", "Patricia Robledo"], "doi"=>["https://dx.doi.org/10.1371/journal.pbio.1002194.g008"], "stats"=>{"downloads"=>0, "page_views"=>0, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Differential_expression_of_CB_1_R_5_HT_2A_R_heteromers_in_the_brain_detected_by_in_situ_PLAs_/1478550", "title"=>"Differential expression of CB<sub>1</sub>R-5-HT<sub>2A</sub>R heteromers in the brain detected by in situ PLAs.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2015-07-09 03:25:07"}
  • {"files"=>["https://ndownloader.figshare.com/files/2169522"], "description"=>"<p>Slices from the hippocampus (A), caudate-putamen (B), cortex (C), and nucleus accumbens (D) of WT mice (white bars) and 5-HT<sub>2A</sub>R KO mice (black bars) were preincubated or not with CB<sub>1</sub>R antagonist rimonabant (1 μM, RIM) or the 5-HT<sub>2A</sub>R antagonist MDL 100,907 (300 nM, MDL) for 20 min before the addition of the CB<sub>1</sub>R agonist WIN 55,212–2 (1 μM, WIN), the 5-HT<sub>2A</sub>R agonist DOI (1 μM), or both for an additional incubation period of 10 min. ERK 1/2 phosphorylation was determined by western blot. Immunoreactive bands from three to seven slices obtained from ten WT or KO animals were quantified for each condition. Values represent mean ± SEM of the percentage of phosphorylation relative to basal levels found in untreated slices. No significant differences were obtained between the basal levels of the WT and the KO mice. One-way ANOVA followed by Bonferroni post hoc tests showed a significant (* <i>p</i> < 0.05, ** <i>p</i> < 0.01, *** <i>p</i> < 0.001) effect over basal or of the antagonist plus agonist treatment over the agonist treatment (# <i>p</i> < 0.05, ## <i>p</i> < 0.01).</p>", "links"=>[], "tags"=>["CB 1R", "cannabinoid CB 1 receptors", "Cannabinoid CB 1", "transmembrane helices 5", "2a", "thc", "ht", "2AR", "impairment", "CB 1R heteromers", "Cognitive Impairment Induced", "antinociceptive effects"], "article_id"=>1478552, "categories"=>["Biological Sciences"], "users"=>["Xavier Viñals", "Estefanía Moreno", "Laurence Lanfumey", "Arnau Cordomí", "Antoni Pastor", "Rafael de la Torre", "Paola Gasperini", "Gemma Navarro", "Lesley A. Howell", "Leonardo Pardo", "Carmen Lluís", "Enric I. Canela", "Peter J. McCormick", "Rafael Maldonado", "Patricia Robledo"], "doi"=>["https://dx.doi.org/10.1371/journal.pbio.1002194.g009"], "stats"=>{"downloads"=>0, "page_views"=>0, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Differential_expression_of_CB_1_R_5_HT_2A_R_heteromers_in_the_brain_detected_by_heteromer_signaling_/1478552", "title"=>"Differential expression of CB<sub>1</sub>R-5-HT<sub>2A</sub>R heteromers in the brain detected by heteromer signaling.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2015-07-09 03:25:07"}
  • {"files"=>["https://ndownloader.figshare.com/files/2169532"], "description"=>"<p>The amnesic effects of THC (3 mg/kg) observed in C57BL/6J mice in the novel object recognition test were abrogated by pretreatment with the 5-HT<sub>2A</sub>R antagonist, MDL 100,907 (0.01 mg/kg) (A) and by pretreatment with TM 5 and TM 6, but not TM 7, interference peptides (0.2 μg/ 2μl ICV) (B) (<i>n</i> = 5–9). The anxiolytic effects of THC (0.3 mg/kg) observed in the elevated plus maze in C57BL/6J mice were blocked by pretreatment with the 5-HT<sub>2A</sub>R antagonist, MDL 100,907 (0.01 mg/kg) (C) and by pretreatment with TM 5 and TM 6, but not TM 7, interference peptides (0.2 μg/ 2μl ICV) (D) (<i>n</i> = 4–11). The data represent mean + SEM. * <i>p</i> < 0.05, ** <i>p</i> < 0.01, *** <i>p</i> < 0.001 versus vehicle, # <i>p</i> < 0.05 versus THC-treated mice. In (E), PLA performed in hippocampal CA3, striatal (caudate-putamen), and cortical (somatomotor layers 1, 2, and 3) slices from mice treated with VEH, TM 6, and TM 7 interference peptides (0.2 μg/ 2μl ICV). Confocal microscopy images (superimposed sections) are shown in which heteromers appear as green spots in VEH and TM 7-treated mice, but not in mice treated with TM 6 interference peptides. In all cases, cell nuclei were stained with DAPI (blue). Scale bars = 20 μm. In (F), the number of cells containing one or more green spots is expressed as the percentage of the total number of cells (blue nucleus) in the hippocampus, striatum, and cortex (top to bottom). Data (percentage of positive cells) are the mean ± SEM of counts in 8–12 different fields. *** <i>p</i> < 0.001 versus vehicle-treated mice. Pretreatment with TM 5, TM 6, or TM 7 peptides (0.2 μg/ 2μl ICV) had no significant effects on hypolocomotion (G), hypothermia (H), or analgesia (I) induced by THC (10 mg/kg) in C57BL/6J mice. The statistical analyses used and their corresponding F and <i>p</i>-values are shown in <a href=\"http://www.plosbiology.org/article/info:doi/10.1371/journal.pbio.1002194#pbio.1002194.s013\" target=\"_blank\">S1 Table</a>.</p>", "links"=>[], "tags"=>["CB 1R", "cannabinoid CB 1 receptors", "Cannabinoid CB 1", "transmembrane helices 5", "2a", "thc", "ht", "2AR", "impairment", "CB 1R heteromers", "Cognitive Impairment Induced", "antinociceptive effects"], "article_id"=>1478561, "categories"=>["Biological Sciences"], "users"=>["Xavier Viñals", "Estefanía Moreno", "Laurence Lanfumey", "Arnau Cordomí", "Antoni Pastor", "Rafael de la Torre", "Paola Gasperini", "Gemma Navarro", "Lesley A. Howell", "Leonardo Pardo", "Carmen Lluís", "Enric I. Canela", "Peter J. McCormick", "Rafael Maldonado", "Patricia Robledo"], "doi"=>["https://dx.doi.org/10.1371/journal.pbio.1002194.g010"], "stats"=>{"downloads"=>0, "page_views"=>0, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Prevention_of_THC_induced_amnesic_and_anxiolytic_like_effects_by_pharmacological_blockade_of_5_HT_2A_R_or_by_CB_1_R_5_HT_2A_R_heteromer_disruption_with_TM_interference_peptides_/1478561", "title"=>"Prevention of THC-induced amnesic and anxiolytic-like effects by pharmacological blockade of 5-HT<sub>2A</sub>R or by CB<sub>1</sub>R-5-HT<sub>2A</sub>R heteromer disruption with TM interference peptides.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2015-07-09 03:25:07"}
  • {"files"=>["https://ndownloader.figshare.com/files/2169555", "https://ndownloader.figshare.com/files/2169557", "https://ndownloader.figshare.com/files/2169558", "https://ndownloader.figshare.com/files/2169559", "https://ndownloader.figshare.com/files/2169560", "https://ndownloader.figshare.com/files/2169561", "https://ndownloader.figshare.com/files/2169562", "https://ndownloader.figshare.com/files/2169563", "https://ndownloader.figshare.com/files/2169564", "https://ndownloader.figshare.com/files/2169565", "https://ndownloader.figshare.com/files/2169566", "https://ndownloader.figshare.com/files/2169567", "https://ndownloader.figshare.com/files/2169568", "https://ndownloader.figshare.com/files/2169569"], "description"=>"<div><p>Activation of cannabinoid CB1 receptors (CB<sub>1</sub>R) by delta9-tetrahydrocannabinol (THC) produces a variety of negative effects with major consequences in cannabis users that constitute important drawbacks for the use of cannabinoids as therapeutic agents. For this reason, there is a tremendous medical interest in harnessing the beneficial effects of THC. Behavioral studies carried out in mice lacking 5-HT<sub>2A</sub> receptors (5-HT<sub>2A</sub>R) revealed a remarkable 5-HT<sub>2A</sub>R-dependent dissociation in the beneficial antinociceptive effects of THC and its detrimental amnesic properties. We found that specific effects of THC such as memory deficits, anxiolytic-like effects, and social interaction are under the control of 5-HT<sub>2A</sub>R, but its acute hypolocomotor, hypothermic, anxiogenic, and antinociceptive effects are not. In biochemical studies, we show that CB<sub>1</sub>R and 5-HT<sub>2A</sub>R form heteromers that are expressed and functionally active in specific brain regions involved in memory impairment. Remarkably, our functional data shows that costimulation of both receptors by agonists reduces cell signaling, antagonist binding to one receptor blocks signaling of the interacting receptor, and heteromer formation leads to a switch in G-protein coupling for 5-HT<sub>2A</sub>R from Gq to Gi proteins. Synthetic peptides with the sequence of transmembrane helices 5 and 6 of CB<sub>1</sub>R, fused to a cell-penetrating peptide, were able to disrupt receptor heteromerization in vivo, leading to a selective abrogation of memory impairments caused by exposure to THC. These data reveal a novel molecular mechanism for the functional interaction between CB<sub>1</sub>R and 5-HT<sub>2A</sub>R mediating cognitive impairment. CB<sub>1</sub>R-5-HT<sub>2A</sub>R heteromers are thus good targets to dissociate the cognitive deficits induced by THC from its beneficial antinociceptive properties.</p></div>", "links"=>[], "tags"=>["CB 1R", "cannabinoid CB 1 receptors", "Cannabinoid CB 1", "transmembrane helices 5", "2a", "thc", "ht", "2AR", "impairment", "CB 1R heteromers", "Cognitive Impairment Induced", "antinociceptive effects"], "article_id"=>1478569, "categories"=>["Biological Sciences"], "users"=>["Xavier Viñals", "Estefanía Moreno", "Laurence Lanfumey", "Arnau Cordomí", "Antoni Pastor", "Rafael de la Torre", "Paola Gasperini", "Gemma Navarro", "Lesley A. Howell", "Leonardo Pardo", "Carmen Lluís", "Enric I. Canela", "Peter J. McCormick", "Rafael Maldonado", "Patricia Robledo"], "doi"=>["https://dx.doi.org/10.1371/journal.pbio.1002194.s001", "https://dx.doi.org/10.1371/journal.pbio.1002194.s002", "https://dx.doi.org/10.1371/journal.pbio.1002194.s003", "https://dx.doi.org/10.1371/journal.pbio.1002194.s004", "https://dx.doi.org/10.1371/journal.pbio.1002194.s005", "https://dx.doi.org/10.1371/journal.pbio.1002194.s006", "https://dx.doi.org/10.1371/journal.pbio.1002194.s007", "https://dx.doi.org/10.1371/journal.pbio.1002194.s008", "https://dx.doi.org/10.1371/journal.pbio.1002194.s009", "https://dx.doi.org/10.1371/journal.pbio.1002194.s010", "https://dx.doi.org/10.1371/journal.pbio.1002194.s011", "https://dx.doi.org/10.1371/journal.pbio.1002194.s012", "https://dx.doi.org/10.1371/journal.pbio.1002194.s013", "https://dx.doi.org/10.1371/journal.pbio.1002194.s014"], "stats"=>{"downloads"=>0, "page_views"=>0, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/Cognitive_Impairment_Induced_by_Delta9_tetrahydrocannabinol_Occurs_through_Heteromers_between_Cannabinoid_CB_1_and_Serotonin_5_HT_2A_Receptors/1478569", "title"=>"Cognitive Impairment Induced by Delta9-tetrahydrocannabinol Occurs through Heteromers between Cannabinoid CB<sub>1</sub> and Serotonin 5-HT<sub>2A</sub> Receptors", "pos_in_sequence"=>0, "defined_type"=>4, "published_date"=>"2015-07-09 03:25:07"}

PMC Usage Stats | Further Information

  • {"unique-ip"=>"142", "full-text"=>"62", "pdf"=>"296", "abstract"=>"0", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"7", "supp-data"=>"99", "cited-by"=>"0", "year"=>"2015", "month"=>"7"}
  • {"unique-ip"=>"100", "full-text"=>"98", "pdf"=>"70", "abstract"=>"0", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"7", "supp-data"=>"16", "cited-by"=>"0", "year"=>"2015", "month"=>"8"}
  • {"unique-ip"=>"74", "full-text"=>"81", "pdf"=>"50", "abstract"=>"0", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"16", "supp-data"=>"66", "cited-by"=>"0", "year"=>"2015", "month"=>"9"}
  • {"unique-ip"=>"76", "full-text"=>"65", "pdf"=>"52", "abstract"=>"0", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"24", "supp-data"=>"2", "cited-by"=>"0", "year"=>"2015", "month"=>"10"}
  • {"unique-ip"=>"63", "full-text"=>"54", "pdf"=>"30", "abstract"=>"0", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"5", "supp-data"=>"1", "cited-by"=>"0", "year"=>"2015", "month"=>"11"}
  • {"unique-ip"=>"45", "full-text"=>"46", "pdf"=>"20", "abstract"=>"0", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"23", "supp-data"=>"3", "cited-by"=>"0", "year"=>"2015", "month"=>"12"}
  • {"unique-ip"=>"37", "full-text"=>"40", "pdf"=>"25", "abstract"=>"0", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"9", "supp-data"=>"4", "cited-by"=>"1", "year"=>"2016", "month"=>"1"}
  • {"unique-ip"=>"32", "full-text"=>"35", "pdf"=>"12", "abstract"=>"0", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"9", "supp-data"=>"5", "cited-by"=>"1", "year"=>"2016", "month"=>"2"}
  • {"unique-ip"=>"48", "full-text"=>"70", "pdf"=>"23", "abstract"=>"0", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"22", "supp-data"=>"1", "cited-by"=>"1", "year"=>"2016", "month"=>"3"}
  • {"unique-ip"=>"41", "full-text"=>"38", "pdf"=>"16", "abstract"=>"0", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"5", "supp-data"=>"0", "cited-by"=>"1", "year"=>"2016", "month"=>"4"}
  • {"unique-ip"=>"33", "full-text"=>"32", "pdf"=>"17", "abstract"=>"0", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"2", "supp-data"=>"0", "cited-by"=>"0", "year"=>"2016", "month"=>"5"}
  • {"unique-ip"=>"29", "full-text"=>"35", "pdf"=>"12", "abstract"=>"0", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"5", "supp-data"=>"0", "cited-by"=>"0", "year"=>"2016", "month"=>"7"}
  • {"unique-ip"=>"33", "full-text"=>"32", "pdf"=>"12", "abstract"=>"0", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"12", "supp-data"=>"0", "cited-by"=>"1", "year"=>"2016", "month"=>"8"}
  • {"unique-ip"=>"45", "full-text"=>"43", "pdf"=>"14", "abstract"=>"0", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"38", "supp-data"=>"9", "cited-by"=>"1", "year"=>"2016", "month"=>"9"}
  • {"unique-ip"=>"41", "full-text"=>"43", "pdf"=>"24", "abstract"=>"0", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"4", "supp-data"=>"14", "cited-by"=>"0", "year"=>"2016", "month"=>"10"}
  • {"unique-ip"=>"40", "full-text"=>"50", "pdf"=>"15", "abstract"=>"0", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"17", "supp-data"=>"44", "cited-by"=>"0", "year"=>"2016", "month"=>"11"}
  • {"unique-ip"=>"11", "full-text"=>"11", "pdf"=>"5", "abstract"=>"0", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"3", "supp-data"=>"0", "cited-by"=>"0", "year"=>"2016", "month"=>"12"}
  • {"unique-ip"=>"28", "full-text"=>"32", "pdf"=>"10", "abstract"=>"0", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"28", "supp-data"=>"0", "cited-by"=>"1", "year"=>"2017", "month"=>"1"}
  • {"unique-ip"=>"20", "full-text"=>"22", "pdf"=>"12", "abstract"=>"0", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"2", "supp-data"=>"0", "cited-by"=>"0", "year"=>"2017", "month"=>"2"}
  • {"unique-ip"=>"26", "full-text"=>"29", "pdf"=>"13", "abstract"=>"0", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"5", "supp-data"=>"0", "cited-by"=>"0", "year"=>"2017", "month"=>"3"}
  • {"unique-ip"=>"17", "full-text"=>"26", "pdf"=>"5", "abstract"=>"0", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"1", "supp-data"=>"0", "cited-by"=>"0", "year"=>"2017", "month"=>"4"}
  • {"unique-ip"=>"21", "full-text"=>"23", "pdf"=>"13", "abstract"=>"0", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"3", "supp-data"=>"0", "cited-by"=>"0", "year"=>"2017", "month"=>"5"}
  • {"unique-ip"=>"25", "full-text"=>"27", "pdf"=>"14", "abstract"=>"0", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"6", "supp-data"=>"0", "cited-by"=>"0", "year"=>"2017", "month"=>"6"}
  • {"unique-ip"=>"17", "full-text"=>"19", "pdf"=>"4", "abstract"=>"0", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"1", "supp-data"=>"0", "cited-by"=>"0", "year"=>"2017", "month"=>"7"}
  • {"unique-ip"=>"20", "full-text"=>"21", "pdf"=>"13", "abstract"=>"0", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"11", "supp-data"=>"0", "cited-by"=>"0", "year"=>"2017", "month"=>"8"}
  • {"unique-ip"=>"24", "full-text"=>"30", "pdf"=>"11", "abstract"=>"0", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"2", "supp-data"=>"0", "cited-by"=>"0", "year"=>"2017", "month"=>"9"}
  • {"unique-ip"=>"13", "full-text"=>"14", "pdf"=>"3", "abstract"=>"0", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"2", "supp-data"=>"1", "cited-by"=>"0", "year"=>"2017", "month"=>"10"}
  • {"unique-ip"=>"20", "full-text"=>"23", "pdf"=>"3", "abstract"=>"0", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"0", "supp-data"=>"1", "cited-by"=>"0", "year"=>"2017", "month"=>"11"}
  • {"unique-ip"=>"18", "full-text"=>"22", "pdf"=>"5", "abstract"=>"0", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"0", "supp-data"=>"0", "cited-by"=>"0", "year"=>"2017", "month"=>"12"}
  • {"unique-ip"=>"30", "full-text"=>"35", "pdf"=>"14", "abstract"=>"0", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"6", "supp-data"=>"0", "cited-by"=>"0", "year"=>"2018", "month"=>"1"}
  • {"unique-ip"=>"29", "full-text"=>"29", "pdf"=>"20", "abstract"=>"0", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"4", "supp-data"=>"0", "cited-by"=>"0", "year"=>"2018", "month"=>"3"}
  • {"unique-ip"=>"29", "full-text"=>"34", "pdf"=>"5", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"5", "supp-data"=>"0", "cited-by"=>"0", "year"=>"2019", "month"=>"1"}
  • {"unique-ip"=>"25", "full-text"=>"30", "pdf"=>"6", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"12", "supp-data"=>"0", "cited-by"=>"0", "year"=>"2018", "month"=>"5"}
  • {"unique-ip"=>"15", "full-text"=>"16", "pdf"=>"4", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"3", "supp-data"=>"0", "cited-by"=>"0", "year"=>"2018", "month"=>"6"}
  • {"unique-ip"=>"17", "full-text"=>"17", "pdf"=>"11", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"0", "supp-data"=>"0", "cited-by"=>"0", "year"=>"2018", "month"=>"4"}
  • {"unique-ip"=>"33", "full-text"=>"31", "pdf"=>"11", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"0", "supp-data"=>"4", "cited-by"=>"2", "year"=>"2018", "month"=>"7"}
  • {"unique-ip"=>"18", "full-text"=>"23", "pdf"=>"4", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"1", "supp-data"=>"3", "cited-by"=>"0", "year"=>"2018", "month"=>"8"}
  • {"unique-ip"=>"28", "full-text"=>"34", "pdf"=>"5", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"1", "supp-data"=>"0", "cited-by"=>"0", "year"=>"2018", "month"=>"9"}
  • {"unique-ip"=>"20", "full-text"=>"19", "pdf"=>"8", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"2", "supp-data"=>"0", "cited-by"=>"0", "year"=>"2018", "month"=>"10"}
  • {"unique-ip"=>"39", "full-text"=>"39", "pdf"=>"11", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"12", "supp-data"=>"2", "cited-by"=>"0", "year"=>"2018", "month"=>"11"}
  • {"unique-ip"=>"15", "full-text"=>"17", "pdf"=>"4", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"0", "supp-data"=>"1", "cited-by"=>"0", "year"=>"2018", "month"=>"12"}
  • {"unique-ip"=>"20", "full-text"=>"24", "pdf"=>"9", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"2", "supp-data"=>"0", "cited-by"=>"0", "year"=>"2019", "month"=>"2"}
  • {"unique-ip"=>"32", "full-text"=>"32", "pdf"=>"6", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"2", "supp-data"=>"1", "cited-by"=>"0", "year"=>"2019", "month"=>"3"}
  • {"unique-ip"=>"49", "full-text"=>"51", "pdf"=>"12", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"1", "supp-data"=>"1", "cited-by"=>"0", "year"=>"2019", "month"=>"4"}
  • {"unique-ip"=>"55", "full-text"=>"39", "pdf"=>"8", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"15", "supp-data"=>"6", "cited-by"=>"1", "year"=>"2019", "month"=>"5"}
  • {"unique-ip"=>"29", "full-text"=>"28", "pdf"=>"11", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"21", "supp-data"=>"2", "cited-by"=>"0", "year"=>"2019", "month"=>"8"}
  • {"unique-ip"=>"43", "full-text"=>"51", "pdf"=>"5", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"15", "supp-data"=>"0", "cited-by"=>"0", "year"=>"2019", "month"=>"9"}
  • {"unique-ip"=>"47", "full-text"=>"54", "pdf"=>"18", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"29", "supp-data"=>"9", "cited-by"=>"0", "year"=>"2019", "month"=>"10"}
  • {"unique-ip"=>"18", "full-text"=>"22", "pdf"=>"6", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"0", "supp-data"=>"17", "cited-by"=>"0", "year"=>"2019", "month"=>"12"}
  • {"unique-ip"=>"26", "full-text"=>"26", "pdf"=>"8", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"0", "supp-data"=>"15", "cited-by"=>"0", "year"=>"2020", "month"=>"2"}
  • {"unique-ip"=>"28", "full-text"=>"36", "pdf"=>"6", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"7", "supp-data"=>"18", "cited-by"=>"0", "year"=>"2020", "month"=>"3"}
  • {"unique-ip"=>"25", "full-text"=>"31", "pdf"=>"11", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"6", "supp-data"=>"0", "cited-by"=>"0", "year"=>"2020", "month"=>"4"}
  • {"unique-ip"=>"26", "full-text"=>"37", "pdf"=>"5", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"2", "supp-data"=>"0", "cited-by"=>"0", "year"=>"2020", "month"=>"5"}
  • {"unique-ip"=>"30", "full-text"=>"32", "pdf"=>"10", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"20", "supp-data"=>"3", "cited-by"=>"1", "year"=>"2020", "month"=>"6"}
  • {"unique-ip"=>"26", "full-text"=>"43", "pdf"=>"3", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"0", "supp-data"=>"0", "cited-by"=>"1", "year"=>"2020", "month"=>"7"}
  • {"unique-ip"=>"27", "full-text"=>"26", "pdf"=>"7", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"0", "supp-data"=>"0", "cited-by"=>"0", "year"=>"2020", "month"=>"8"}
  • {"unique-ip"=>"17", "full-text"=>"17", "pdf"=>"8", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"0", "supp-data"=>"0", "cited-by"=>"0", "year"=>"2020", "month"=>"9"}
  • {"unique-ip"=>"24", "full-text"=>"27", "pdf"=>"6", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"0", "supp-data"=>"3", "cited-by"=>"0", "year"=>"2020", "month"=>"10"}

Relative Metric

{"start_date"=>"2015-01-01T00:00:00Z", "end_date"=>"2015-12-31T00:00:00Z", "subject_areas"=>[]}

F1000Prime | Further Information

Loading … Spinner
There are currently no alerts