A Neuronal Acetylcholine Receptor Regulates the Balance of Muscle Excitation and Inhibition in Caenorhabditis elegans
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{"title"=>"A neuronal acetylcholine receptor regulates the balance of muscle excitation and inhibition in Caenorhabditis elegans", "type"=>"journal", "authors"=>[{"first_name"=>"Maelle", "last_name"=>"Jospin", "scopus_author_id"=>"6506139724"}, {"first_name"=>"Yingchuan B.", "last_name"=>"Qi", "scopus_author_id"=>"35620967600"}, {"first_name"=>"Tamara M.", "last_name"=>"Stawicki", "scopus_author_id"=>"9041694600"}, {"first_name"=>"Thomas", "last_name"=>"Boulin", "scopus_author_id"=>"7801648081"}, {"first_name"=>"Kim R.", "last_name"=>"Schuske", "scopus_author_id"=>"6603215394"}, {"first_name"=>"H. Robert", "last_name"=>"Horvitz", "scopus_author_id"=>"7007006983"}, {"first_name"=>"Jean Louis", "last_name"=>"Bessereau", "scopus_author_id"=>"6602678275"}, {"first_name"=>"Erik M.", "last_name"=>"Jorgensen", "scopus_author_id"=>"26643270100"}, {"first_name"=>"Yishi", "last_name"=>"Jin", "scopus_author_id"=>"7404457596"}], "year"=>2009, "source"=>"PLoS Biology", "identifiers"=>{"scopus"=>"2-s2.0-73949099851", "pmid"=>"20027209", "sgr"=>"73949099851", "doi"=>"10.1371/journal.pbio.1000265", "isbn"=>"1545-7885 (Electronic)\\r1544-9173 (Linking)", "issn"=>"15449173", "pui"=>"358096223"}, "id"=>"9cea24ef-22aa-3c1c-8445-80aec33a00e9", "abstract"=>"In the nematode Caenorhabditis elegans, cholinergic motor neurons stimulate muscle contraction as well as activate GABAergic motor neurons that inhibit contraction of the contralateral muscles. Here, we describe the composition of an ionotropic acetylcholine receptor that is required to maintain excitation of the cholinergic motor neurons. We identified a gain-of-function mutation that leads to spontaneous muscle convulsions. The mutation is in the pore domain of the ACR-2 acetylcholine receptor subunit and is identical to a hyperactivating mutation in the muscle receptor of patients with myasthenia gravis. Screens for suppressors of the convulsion phenotype led to the identification of other receptor subunits. Cell-specific rescue experiments indicate that these subunits function in the cholinergic motor neurons. Expression of these subunits in Xenopus oocytes demonstrates that the functional receptor is comprised of three alpha-subunits, UNC-38, UNC-63 and ACR-12, and two non-alpha-subunits, ACR-2 and ACR-3. Although this receptor exhibits a partially overlapping subunit composition with the C. elegans muscle acetylcholine receptor, it shows distinct pharmacology. Recordings from intact animals demonstrate that loss-of-function mutations in acr-2 reduce the excitability of the cholinergic motor neurons. By contrast, the acr-2(gf) mutation leads to a hyperactivation of cholinergic motor neurons and an inactivation of downstream GABAergic motor neurons in a calcium dependent manner. Presumably, this imbalance between excitatory and inhibitory input into muscles leads to convulsions. These data indicate that the ACR-2 receptor is important for the coordinated excitation and inhibition of body muscles underlying sinusoidal movement.", "link"=>"http://www.mendeley.com/research/neuronal-acetylcholine-receptor-regulates-balance-muscle-excitation-inhibition-caenorhabditis-elegan", "reader_count"=>82, "reader_count_by_academic_status"=>{"Unspecified"=>2, "Professor > Associate Professor"=>7, "Librarian"=>1, "Researcher"=>20, "Student > Doctoral Student"=>2, "Student > Ph. D. Student"=>27, "Student > Postgraduate"=>4, "Student > Master"=>2, "Other"=>4, "Student > Bachelor"=>9, "Professor"=>4}, "reader_count_by_user_role"=>{"Unspecified"=>2, "Professor > Associate Professor"=>7, "Librarian"=>1, "Researcher"=>20, "Student > Doctoral Student"=>2, "Student > Ph. D. Student"=>27, "Student > Postgraduate"=>4, "Student > Master"=>2, "Other"=>4, "Student > Bachelor"=>9, "Professor"=>4}, "reader_count_by_subject_area"=>{"Engineering"=>1, "Unspecified"=>2, "Biochemistry, Genetics and Molecular Biology"=>5, "Agricultural and Biological Sciences"=>61, "Medicine and Dentistry"=>1, "Neuroscience"=>9, "Physics and Astronomy"=>2, "Computer Science"=>1}, "reader_count_by_subdiscipline"=>{"Engineering"=>{"Engineering"=>1}, "Medicine and Dentistry"=>{"Medicine and Dentistry"=>1}, "Neuroscience"=>{"Neuroscience"=>9}, "Physics and Astronomy"=>{"Physics and Astronomy"=>2}, "Agricultural and Biological Sciences"=>{"Agricultural and Biological Sciences"=>61}, "Computer Science"=>{"Computer Science"=>1}, "Biochemistry, Genetics and Molecular Biology"=>{"Biochemistry, Genetics and Molecular Biology"=>5}, "Unspecified"=>{"Unspecified"=>2}}, "reader_count_by_country"=>{"Canada"=>3, "United States"=>9, "Brazil"=>1, "Switzerland"=>1, "Germany"=>1}, "group_count"=>4}

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  • {"files"=>["https://ndownloader.figshare.com/files/870611"], "description"=>"<p>(A) The ACR-2R receptor shows high sensitivity to acetylcholine and is insensitive to levamisole or choline. Mecamylamine completely blocks the current. The ACR-2R receptor includes all five subunits. (B) The ACR-2(V13'M)R receptor shows high sensitivity to acetylcholine and an increased sensitivity to DMPP, and weakly responds to levamisole and choline. The ACR-2(V13'M)R receptor includes all five subunits. (C) Quantification of the relative efficacies of cholinergic agonists compared to acetylcholine. Numbers above the bars represent the numbers of oocytes recorded for each condition. Example of traces are shown in (A and B). Replacement of ACR-2(+) by ACR-2(n2420) increased agonist efficacy for DMPP, choline, and levamisole, whereas nicotine efficacy was unchanged. ACh: 100 µM acetylcholine; Nic: 100 µM nicotine; DMPP: 100 µM DMPP; Cho: 1 mM choline; and Lev: 100 µM levamisole. (D) Inclusion of ACR-3 greatly increases the current of the ACR-2R. cRNAs for <i>acr-12</i>, <i>ric-3</i>, <i>unc-38</i>, <i>unc-50</i>, <i>unc-63</i>, and <i>unc-74</i> were coinjected for each condition. Average peak current for <i>acr-2 </i>+ <i>acr-3</i> coinjection was 111±68 nA (<i>n</i> = 34). (E) Dose–response curves for acetylcholine action on the ACR-2 and ACR-2(V13'M) receptors show that EC50 is comparable. All recordings were made with 1 mM external CaCl<sub>2</sub>. Error bars are standard errors of the mean. Asterisks indicate that data are significantly different at <i>p</i><0.05 (*) or <i>p</i><0.01 (**). ACh: acetylcholine; Nic: nicotine; DMPP: 1,1-dimethyl-4-phenylpiperazinium; Cho: choline; Lev: levamisole; Mec: mecamylamine.</p>", "links"=>[], "tags"=>["acr-2r", "receptor", "reconstituted"], "article_id"=>541061, "categories"=>["Genetics", "Neuroscience"], "users"=>["Maelle Jospin", "Yingchuan B. Qi", "Tamara M. Stawicki", "Thomas Boulin", "Kim R. Schuske", "H. Robert Horvitz", "Jean-Louis Bessereau", "Erik M. Jorgensen", "Yishi Jin"], "doi"=>"https://dx.doi.org/10.1371/journal.pbio.1000265.g007", "stats"=>{"downloads"=>0, "page_views"=>10, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Composition_of_the_ACR_2R_receptor_reconstituted_in_Xenopus_oocytes_/541061", "title"=>"Composition of the ACR-2R receptor reconstituted in <i>Xenopus</i> oocytes.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2009-12-22 00:17:41"}
  • {"files"=>["https://ndownloader.figshare.com/files/870167"], "description"=>"<p>(A) Expression pattern from a 3.5-kb <i>acr-2</i> promoter-driven <i>Pacr-2-GFP</i> transgene (<i>juIs14</i>) in an L1 (upper image) and an L4 larva. Middle image is a side view, and the bottom image is a ventral view of an L4 larva. The number and positions of the cells and the sides of the commissures indicate that they are embryonically born DA and DB and postembryonically born VA and VB neurons. Expression is also seen in DVC in the tail (arrow, middle panel). Scale bars indicate 10 µm. (B). The top image shows nonoverlapping expression of <i>Pacr-2-GFP</i> (<i>juIs14</i>) (green) and <i>Pttr-39-mcherry</i> (<i>juIs223</i>) (red) marking the DD and VD GABAergic neurons. The bottom images show nonoverlapping expression of the 1.8-kb promoter-driven <i>Pacr-2-mcherry</i> transgene (<i>juEx2045</i>) (red) and those of <i>Pglr-1-GFP</i> (<i>nuIs1</i>) (green) or <i>Pnmr-1-GFP</i> (<i>akIs3</i>) (green), which label the command interneurons in the head (left panels) and tail (right panels) ganglia. Transcriptional activity of the <i>acr-2</i> 1.8-kb promoter is not seen in any head neurons. Scale bars indicate 10 µm. (C) Quantification of cell-type–specific transgenic rescue of the convulsion defects in <i>acr-2(n2420gf)</i> animals. <i>Pacr-2::acr-2</i> contains the full-length genomic coding sequence driven by the 3.5-kb-long promoter. P<i>acr-2::acr-2(mini)</i> contains cDNA that replaced genomic DNA from exon 2, driven by the 1.8-kb promoter. <i>Punc-25::acr-2</i> contains the full-length genomic coding sequences driven by the 1.4-kb <i>unc-25</i> promoter. <i>n</i> = 10, 10, 5, 10, and 8 for N2, <i>acr-2(n2420gf)</i>, <i>acr-2(n2420gf);Pacr-2-acr-2(oxEx707)</i>, <i>acr-2(n2420gf); Pacr-2-acr-2(mini) (juEx2336)</i>, and <i>acr-2(n2420gf);Punc-25-acr-2(juEx32)</i>, respectively.</p>", "links"=>[], "tags"=>["functions", "cholinergic", "ventral"], "article_id"=>540617, "categories"=>["Genetics", "Neuroscience"], "users"=>["Maelle Jospin", "Yingchuan B. Qi", "Tamara M. Stawicki", "Thomas Boulin", "Kim R. Schuske", "H. Robert Horvitz", "Jean-Louis Bessereau", "Erik M. Jorgensen", "Yishi Jin"], "doi"=>"https://dx.doi.org/10.1371/journal.pbio.1000265.g003", "stats"=>{"downloads"=>0, "page_views"=>1, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_acr_2_is_expressed_and_functions_in_the_cholinergic_ventral_cord_motor_neurons_/540617", "title"=>"<i>acr-2</i> is expressed and functions in the cholinergic ventral cord motor neurons.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2009-12-22 00:10:17"}
  • {"files"=>["https://ndownloader.figshare.com/files/869979"], "description"=>"<p>(A) Genetic position of <i>acr-2</i> on the left arm of the X chromosome. (B) Representative cosmids and subclones used in germline transformation rescue of <i>acr-2(n2420gf)</i>. Rescue of spontaneous convulsion is indicated by a plus sign (+); and no rescue by a minus sign (−). Canonical cosmids F38B6 and K11G12 are shown in parentheses. (C) ACR-2 is a member of the UNC-29 class non–α-subunits of the acetylcholine receptor family <a href=\"http://www.plosbiology.org/article/info:doi/10.1371/journal.pbio.1000265#pbio.1000265-Jones2\" target=\"_blank\">[14]</a>. (D) The <i>n2420</i> mutation causes a valine-to-methionine change in the 13′ position of the pore-forming second transmembrane domain (TM2, residues are colored in teal). The amino acid at the 13′ position is oriented toward the pore; orange mark residues lining the pore <a href=\"http://www.plosbiology.org/article/info:doi/10.1371/journal.pbio.1000265#pbio.1000265-Keramidas1\" target=\"_blank\">[20]</a>.</p>", "links"=>[], "tags"=>["genetics and genomics/gene function", "neuroscience/behavioral neuroscience"], "article_id"=>540433, "categories"=>["Genetics", "Neuroscience"], "users"=>["Maelle Jospin", "Yingchuan B. Qi", "Tamara M. Stawicki", "Thomas Boulin", "Kim R. Schuske", "H. Robert Horvitz", "Jean-Louis Bessereau", "Erik M. Jorgensen", "Yishi Jin"], "doi"=>"https://dx.doi.org/10.1371/journal.pbio.1000265.g001", "stats"=>{"downloads"=>1, "page_views"=>4, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_acr_2_locus_/540433", "title"=>"<i>acr-2</i> locus.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2009-12-22 00:07:13"}
  • {"files"=>["https://ndownloader.figshare.com/files/870364"], "description"=>"<p>(A) Representative traces (upper panel) and frequencies (lower panel) of endogenous postsynaptic currents recorded at two holding potentials, −60 and −10 mV, from wild-type and <i>acr-2(n2420gf)</i> worms in 0.5 mM external CaCl<sub>2</sub>. The frequency of miniature postsynaptic currents from cholinergic neurons is increased in the gain-of-function mutant (wild type: 12.1 events/s±1.1 SEM, <i>n</i> = 8; <i>acr-2(n2420gf)</i>: 18.3 events/s±2.2 SEM, <i>n</i> = 9; *<i>p</i> = 0.0307). The frequency of miniature currents induced by GABAergic motor neurons was only slightly reduced in the gain-of-function mutant (wild type: 9.2 events/s±2.3 SEM, <i>n</i> = 8; <i>acr-2(n2420gf)</i>: 7.2 events/s±2.1 SEM, <i>n</i> = 9; <i>p</i> = 0.5342). Data were analyzed using a two-tailed unpaired <i>t</i>-test. (B) Representative traces (upper panel) and frequencies (lower panel) of endogenous postsynaptic currents recorded at two holding potentials, −60 and −10 mV, from wild-type and <i>acr-2(n2420gf)</i> worms in 2 mM external CaCl<sub>2</sub>. Acetylcholine currents frequencies recorded from the wild type (18.9 events/s±2.3 SEM, <i>n</i> = 10) and <i>acr-2(n2420gf)</i> (18.7 events/s±2.6 SEM, <i>n</i> = 14) are not significantly different (<i>p</i> = 0.9555). GABA currents recorded from the wild type (9.9 events/s±1.7 SEM, <i>n</i> = 10) and <i>acr-2(n2420gf)</i> (1.2 events/s±0.6 SEM, <i>n</i> = 14) are significantly different (*<i>p</i> = 0.0007). Data were analyzed using a two-tailed unpaired <i>t</i>-test with Welch's correction. (C) Representative traces (upper panel) and frequencies (lower panel) of endogenous postsynaptic currents recorded at two holding potentials, −60 and −10 mV, from wild-type and <i>acr-2(n2420gf)</i> worms in 5 mM external CaCl<sub>2</sub>. Acetylcholine currents frequencies recorded from the wild type (24.9 events/s±3.4 SEM, <i>n</i> = 8) and <i>acr-2(n2420gf)</i> (7.6 events/s±2.7 SEM, <i>n</i> = 7) are significantly different (*<i>p</i> = 0.0017). GABA currents recorded from the wild type (13.4 events/s±2.0 SEM, <i>n</i> = 8) and <i>acr-2(n2420gf)</i> (2.3 events/s±1.0 SEM, <i>n</i> = 7) are significantly different (**<i>p</i> = 0.0004). Data were analyzed using a two-tailed unpaired <i>t</i>-test.</p>", "links"=>[], "tags"=>["mutants", "reduced", "gaba"], "article_id"=>540822, "categories"=>["Genetics", "Neuroscience"], "users"=>["Maelle Jospin", "Yingchuan B. Qi", "Tamara M. Stawicki", "Thomas Boulin", "Kim R. Schuske", "H. Robert Horvitz", "Jean-Louis Bessereau", "Erik M. Jorgensen", "Yishi Jin"], "doi"=>"https://dx.doi.org/10.1371/journal.pbio.1000265.g005", "stats"=>{"downloads"=>1, "page_views"=>5, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_acr_2_n2420gf_mutants_exhibit_reduced_GABA_neurotransmission_/540822", "title"=>"<i>acr-2(n2420gf)</i> mutants exhibit reduced GABA neurotransmission.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2009-12-22 00:13:42"}
  • {"files"=>["https://ndownloader.figshare.com/files/870726"], "description"=>"<p>Ach, acetylcholine; EC<sub>50</sub>, median effective concentration.</p>", "links"=>[], "tags"=>["acr-2r", "levamisole-sensitive"], "article_id"=>541178, "categories"=>["Genetics", "Neuroscience"], "users"=>["Maelle Jospin", "Yingchuan B. Qi", "Tamara M. Stawicki", "Thomas Boulin", "Kim R. Schuske", "H. Robert Horvitz", "Jean-Louis Bessereau", "Erik M. Jorgensen", "Yishi Jin"], "doi"=>"https://dx.doi.org/10.1371/journal.pbio.1000265.t001", "stats"=>{"downloads"=>0, "page_views"=>60, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Comparison_of_ACR_2R_and_levamisole_sensitive_receptors_/541178", "title"=>"Comparison of ACR-2R and levamisole-sensitive receptors.", "pos_in_sequence"=>0, "defined_type"=>3, "published_date"=>"2009-12-22 00:19:38"}
  • {"files"=>["https://ndownloader.figshare.com/files/870278"], "description"=>"<p>(A) <i>acr-2</i> gene structure with the intragenic mutations identified from the <i>acr-2(n2420gf)</i> suppressor screen. <i>acr-2(n2595 n2420)</i> contains a nonsense mutation at the codon for tryptophan 175 in addition to the original gain-of-function mutation and is used as the null mutant in this figure. <i>ok1887</i> removes the first three exons and inserts 420 bp of unrelated DNA. Details of the nucleotide and amino acid changes are shown in <a href=\"http://www.plosbiology.org/article/info:doi/10.1371/journal.pbio.1000265#pbio.1000265.s008\" target=\"_blank\">Table S1</a> and <a href=\"http://www.plosbiology.org/article/info:doi/10.1371/journal.pbio.1000265#pbio.1000265.s002\" target=\"_blank\">Figure S1</a>. Boxes indicate exons; lines, introns; M, transmembrane domain; an asterisk (*) indicates mutations at the splice junctions; X indicates stop codon mutations. (B) Average speed of wild-type (3.9 mm/min±0.3 SEM, <i>n</i> = 16), <i>acr-2(n2595 n2420)</i> (2.8 mm/min±0.1 SEM, <i>n</i> = 16), and <i>acr-2(n2595 n2420)</i> worms carrying a <i>Pacr-2::acr-2</i> construct (4.0 mm/min±0.4 SEM, <i>n</i> = 16). An ANOVA test followed by a Dunn's post test was used to analyze the data; *<i>p</i><0.05. (C) Acetylcholine mini frequencies recorded in 2 mM external CaCl<sub>2</sub> from the wild type (21.9 events/s±3.2 SEM, <i>n</i> = 5) and <i>acr-2(n2595 n2420)</i> (12.9 events/s±1.6 SEM, <i>n</i> = 9) are significantly different (*<i>p</i> = 0.015). GABA mini frequencies recorded in 2 mM external CaCl<sub>2</sub> from the wild type (14.9 events/s±5.4 SEM, <i>n</i> = 5) and <i>acr-2(n2595 n2420)</i> (10.4 events/s±2.2 SEM, <i>n</i> = 9) are not significantly different (<i>p</i> = 0.38). Data were analyzed using a two-tailed unpaired <i>t</i>-test. (D) Representative traces of minis recorded at two holding potentials, −60 and −10 mV, on body muscle cells from wild-type and <i>acr-2(n2595 n2420)</i> worms in 2 mM external CaCl<sub>2</sub>.</p>", "links"=>[], "tags"=>["neurotransmission", "reduced", "null"], "article_id"=>540726, "categories"=>["Genetics", "Neuroscience"], "users"=>["Maelle Jospin", "Yingchuan B. Qi", "Tamara M. Stawicki", "Thomas Boulin", "Kim R. Schuske", "H. Robert Horvitz", "Jean-Louis Bessereau", "Erik M. Jorgensen", "Yishi Jin"], "doi"=>"https://dx.doi.org/10.1371/journal.pbio.1000265.g004", "stats"=>{"downloads"=>1, "page_views"=>3, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Acetylcholine_neurotransmission_is_reduced_in_acr_2_null_mutants_/540726", "title"=>"Acetylcholine neurotransmission is reduced in <i>acr-2</i> null mutants.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2009-12-22 00:12:06"}
  • {"files"=>["https://ndownloader.figshare.com/files/870540"], "description"=>"<p>(A) <i>acr-12</i> gene structure with the loss-of-function mutations identified as extragenic suppressors of <i>acr-2(n2420gf)</i>. <i>ok367</i> has a 1,368-bp deletion and is a null allele of <i>acr-12</i>. Boxes indicate exons; lines, introns; TM, transmembrane. (B) The convulsions of <i>acr-2(n2420gf)</i> mutants are suppressed by loss-of-function mutations in <i>unc-63</i>, <i>unc-38</i>, <i>unc-50</i>, or <i>unc-74</i>, but not in <i>unc-29</i>, <i>lev-1</i>, and several other <i>acr</i> genes tested. The alleles used were <i>unc-63(e384)</i>, <i>unc-38(e284)</i>, <i>unc-50(n2623)</i>, <i>unc-74(n2614)</i>, <i>unc-29(x29)</i>, <i>lev-1(e211)</i>, <i>acr-16(ok789)</i>, <i>acr-5(ok180)</i>, <i>lev-8(ok1519)</i>, <i>ric-3(hm9)</i>, and <i>lev-10(x17)</i>, all of which are null mutations. Red columns represent ancillary proteins, and green columns represent acetylcholine receptor subunits. A minimum of eight to ten animals per genotype were scored. (C) Cell-type–specific transgenic expression of <i>acr-12</i> and <i>unc-63</i> shows that both are required in the ventral cord cholinergic motor neurons to suppress <i>acr-2(n2420gf)</i>. The alleles used were <i>unc-63(e384)</i> and <i>acr-12(ok367)</i>. <i>Pmyo-3</i> promoter drives expression in all body muscles, and <i>Prab-3</i> drives expression in all neurons <a href=\"http://www.plosbiology.org/article/info:doi/10.1371/journal.pbio.1000265#pbio.1000265-Ruaud1\" target=\"_blank\">[49]</a>. The <i>Pacr-2</i> promoter contains 1.8 kb of <i>acr-2</i> upstream sequences driving expression in A and B neurons (<a href=\"http://www.plosbiology.org/article/info:doi/10.1371/journal.pbio.1000265#pbio-1000265-g003\" target=\"_blank\">Figure 3A</a>), and the <i>Punc-25</i> promoter drives expression in the four RME and 19 D neurons <a href=\"http://www.plosbiology.org/article/info:doi/10.1371/journal.pbio.1000265#pbio.1000265-Jin1\" target=\"_blank\">[38]</a>. The colors of the columns represent grouping of genotypes. A minimum of eight to ten animals per genotype were scored.</p>", "links"=>[], "tags"=>["acetylcholine", "receptor", "subunits", "suppress", "convulsions"], "article_id"=>540989, "categories"=>["Genetics", "Neuroscience"], "users"=>["Maelle Jospin", "Yingchuan B. Qi", "Tamara M. Stawicki", "Thomas Boulin", "Kim R. Schuske", "H. Robert Horvitz", "Jean-Louis Bessereau", "Erik M. Jorgensen", "Yishi Jin"], "doi"=>"https://dx.doi.org/10.1371/journal.pbio.1000265.g006", "stats"=>{"downloads"=>1, "page_views"=>4, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Mutations_in_acetylcholine_receptor_subunits_suppress_convulsions_of_acr_2_n2420gf_mutants_/540989", "title"=>"Mutations in acetylcholine receptor subunits suppress convulsions of <i>acr-2(n2420gf)</i> mutants.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2009-12-22 00:16:29"}
  • {"files"=>["https://ndownloader.figshare.com/files/432490", "https://ndownloader.figshare.com/files/432544", "https://ndownloader.figshare.com/files/432595", "https://ndownloader.figshare.com/files/432678", "https://ndownloader.figshare.com/files/433339", "https://ndownloader.figshare.com/files/433392", "https://ndownloader.figshare.com/files/433616", "https://ndownloader.figshare.com/files/433624", "https://ndownloader.figshare.com/files/433640", "https://ndownloader.figshare.com/files/433662", "https://ndownloader.figshare.com/files/433696"], "description"=>"<div><p>In the nematode <em>Caenorhabditis elegans</em>, cholinergic motor neurons stimulate muscle contraction as well as activate GABAergic motor neurons that inhibit contraction of the contralateral muscles. Here, we describe the composition of an ionotropic acetylcholine receptor that is required to maintain excitation of the cholinergic motor neurons. We identified a gain-of-function mutation that leads to spontaneous muscle convulsions. The mutation is in the pore domain of the ACR-2 acetylcholine receptor subunit and is identical to a hyperactivating mutation in the muscle receptor of patients with myasthenia gravis. Screens for suppressors of the convulsion phenotype led to the identification of other receptor subunits. Cell-specific rescue experiments indicate that these subunits function in the cholinergic motor neurons. Expression of these subunits in <em>Xenopus</em> oocytes demonstrates that the functional receptor is comprised of three α-subunits, UNC-38, UNC-63 and ACR-12, and two non–α-subunits, ACR-2 and ACR-3. Although this receptor exhibits a partially overlapping subunit composition with the <em>C. elegans</em> muscle acetylcholine receptor, it shows distinct pharmacology. Recordings from intact animals demonstrate that loss-of-function mutations in <em>acr-2</em> reduce the excitability of the cholinergic motor neurons. By contrast, the <em>acr-2(gf)</em> mutation leads to a hyperactivation of cholinergic motor neurons and an inactivation of downstream GABAergic motor neurons in a calcium dependent manner. Presumably, this imbalance between excitatory and inhibitory input into muscles leads to convulsions. These data indicate that the ACR-2 receptor is important for the coordinated excitation and inhibition of body muscles underlying sinusoidal movement.</p></div>", "links"=>[], "tags"=>["neuronal", "acetylcholine", "receptor", "regulates", "excitation", "inhibition"], "article_id"=>145342, "categories"=>["Genetics", "Neuroscience"], "users"=>["Maelle Jospin", "Yingchuan B. Qi", "Tamara M. Stawicki", "Thomas Boulin", "Kim R. Schuske", "H. Robert Horvitz", "Jean-Louis Bessereau", "Erik M. Jorgensen", "Yishi Jin"], "doi"=>["https://dx.doi.org/10.1371/journal.pbio.1000265.s001", "https://dx.doi.org/10.1371/journal.pbio.1000265.s002", "https://dx.doi.org/10.1371/journal.pbio.1000265.s003", "https://dx.doi.org/10.1371/journal.pbio.1000265.s004", "https://dx.doi.org/10.1371/journal.pbio.1000265.s005", "https://dx.doi.org/10.1371/journal.pbio.1000265.s006", "https://dx.doi.org/10.1371/journal.pbio.1000265.s007", "https://dx.doi.org/10.1371/journal.pbio.1000265.s008", "https://dx.doi.org/10.1371/journal.pbio.1000265.s009", "https://dx.doi.org/10.1371/journal.pbio.1000265.s010", "https://dx.doi.org/10.1371/journal.pbio.1000265.s011"], "stats"=>{"downloads"=>73, "page_views"=>15, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/A_Neuronal_Acetylcholine_Receptor_Regulates_the_Balance_of_Muscle_Excitation_and_Inhibition_in_Caenorhabditis_elegans_/145342", "title"=>"A Neuronal Acetylcholine Receptor Regulates the Balance of Muscle Excitation and Inhibition in <em>Caenorhabditis elegans</em>", "pos_in_sequence"=>0, "defined_type"=>4, "published_date"=>"2009-12-22 01:29:02"}
  • {"files"=>["https://ndownloader.figshare.com/files/870062"], "description"=>"<p>(A) Suppression of the convulsions of <i>acr-2(n2420gf)</i> mutants by exogenous mecamylamine (100 µM). The effects of mecamylamine are reversible. (B) <i>acr-2(n2420gf)</i> mutants are hypersensitive, and <i>acr-2(lf)</i> mutants are moderately resistant to aldicarb. The graph shows the time course of the response of adult hermaphrodites to 0.5 mM aldicarb, from three trials with ten animals per genotype per trial. *<i>p</i><0.001 between wild type and mutants (two-way ANOVA). (C) <i>acr-2(n2420gf)</i> mutants are hypersensitive to levamisole. The graph shows the time course of the response of 1-d-old hermaphrodites to 1 mM levamisole, from three trials with ten animals per genotype per trial. *<i>p</i><0.001 between wild type and <i>acr-2(n2420gf)</i> (two-way ANOVA). (D) Quantification of convulsion rates of 1-d-old hermaphrodites of various genotypes. (E) Developmental onset of the convulsion phenotype of <i>acr-2(n2420gf)</i> animals occurs during the L3 stage. OA, 2-d-old adult; YA, 1-d-old adult.</p>", "links"=>[], "tags"=>["phenotypes", "pharmacological"], "article_id"=>540511, "categories"=>["Genetics", "Neuroscience"], "users"=>["Maelle Jospin", "Yingchuan B. Qi", "Tamara M. Stawicki", "Thomas Boulin", "Kim R. Schuske", "H. Robert Horvitz", "Jean-Louis Bessereau", "Erik M. Jorgensen", "Yishi Jin"], "doi"=>"https://dx.doi.org/10.1371/journal.pbio.1000265.g002", "stats"=>{"downloads"=>1, "page_views"=>4, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Mutant_phenotypes_and_pharmacological_analysis_of_acr_2_n2420gf_mutants_/540511", "title"=>"Mutant phenotypes and pharmacological analysis of <i>acr-2(n2420gf)</i> mutants.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2009-12-22 00:08:31"}

PMC Usage Stats | Further Information

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Relative Metric

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