A Neuronal Acetylcholine Receptor Regulates the Balance of Muscle Excitation and Inhibition in Caenorhabditis elegans
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 exc...
| Main Authors: | , , , , , , , , |
|---|---|
| Other Authors: | |
| Format: | Article |
| Language: | en_US |
| Published: |
Public Library of Science
2010
|
| Online Access: | http://hdl.handle.net/1721.1/52574 https://orcid.org/0000-0002-9964-9613 |
| _version_ | 1826208318170857472 |
|---|---|
| author | Jospin, Maelle Qi, Yingchuan B. Stawicki, Tamara M. Boulin, Thomas Schuske, Kim R. Bessereau, Jean-Louis Jorgensen, Erik M. Jin, Yishi Horvitz, Howard Robert |
| author2 | Massachusetts Institute of Technology. Department of Biology |
| author_facet | Massachusetts Institute of Technology. Department of Biology Jospin, Maelle Qi, Yingchuan B. Stawicki, Tamara M. Boulin, Thomas Schuske, Kim R. Bessereau, Jean-Louis Jorgensen, Erik M. Jin, Yishi Horvitz, Howard Robert |
| author_sort | Jospin, Maelle |
| collection | MIT |
| description | 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 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 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. |
| first_indexed | 2024-09-23T14:03:54Z |
| format | Article |
| id | mit-1721.1/52574 |
| institution | Massachusetts Institute of Technology |
| language | en_US |
| last_indexed | 2024-09-23T14:03:54Z |
| publishDate | 2010 |
| publisher | Public Library of Science |
| record_format | dspace |
| spelling | mit-1721.1/525742022-09-28T18:05:01Z A Neuronal Acetylcholine Receptor Regulates the Balance of Muscle Excitation and Inhibition in Caenorhabditis elegans Jospin, Maelle Qi, Yingchuan B. Stawicki, Tamara M. Boulin, Thomas Schuske, Kim R. Bessereau, Jean-Louis Jorgensen, Erik M. Jin, Yishi Horvitz, Howard Robert Massachusetts Institute of Technology. Department of Biology McGovern Institute for Brain Research at MIT Horvitz, H. Robert Horvitz, H. Robert 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 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 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. 2010-03-15T13:47:19Z 2010-03-15T13:47:19Z 2009-12 2009-03 Article http://purl.org/eprint/type/JournalArticle 1544-9173 http://hdl.handle.net/1721.1/52574 Jospin, Maelle et al. “A Neuronal Acetylcholine Receptor Regulates the Balance of Muscle Excitation and Inhibition in Caenorhabditis elegans.” PLoS Biol 7.12 (2009): e1000265. 20027209 https://orcid.org/0000-0002-9964-9613 en_US http://dx.doi.org/10.1371/journal.pbio.1000265 PLoS Biology Creative Commons Attribution http://creativecommons.org/licenses/by/2.5/ application/pdf Public Library of Science PLoS |
| spellingShingle | Jospin, Maelle Qi, Yingchuan B. Stawicki, Tamara M. Boulin, Thomas Schuske, Kim R. Bessereau, Jean-Louis Jorgensen, Erik M. Jin, Yishi Horvitz, Howard Robert A Neuronal Acetylcholine Receptor Regulates the Balance of Muscle Excitation and Inhibition in Caenorhabditis elegans |
| title | A Neuronal Acetylcholine Receptor Regulates the Balance of Muscle Excitation and Inhibition in Caenorhabditis elegans |
| title_full | A Neuronal Acetylcholine Receptor Regulates the Balance of Muscle Excitation and Inhibition in Caenorhabditis elegans |
| title_fullStr | A Neuronal Acetylcholine Receptor Regulates the Balance of Muscle Excitation and Inhibition in Caenorhabditis elegans |
| title_full_unstemmed | A Neuronal Acetylcholine Receptor Regulates the Balance of Muscle Excitation and Inhibition in Caenorhabditis elegans |
| title_short | A Neuronal Acetylcholine Receptor Regulates the Balance of Muscle Excitation and Inhibition in Caenorhabditis elegans |
| title_sort | neuronal acetylcholine receptor regulates the balance of muscle excitation and inhibition in caenorhabditis elegans |
| url | http://hdl.handle.net/1721.1/52574 https://orcid.org/0000-0002-9964-9613 |
| work_keys_str_mv | AT jospinmaelle aneuronalacetylcholinereceptorregulatesthebalanceofmuscleexcitationandinhibitionincaenorhabditiselegans AT qiyingchuanb aneuronalacetylcholinereceptorregulatesthebalanceofmuscleexcitationandinhibitionincaenorhabditiselegans AT stawickitamaram aneuronalacetylcholinereceptorregulatesthebalanceofmuscleexcitationandinhibitionincaenorhabditiselegans AT boulinthomas aneuronalacetylcholinereceptorregulatesthebalanceofmuscleexcitationandinhibitionincaenorhabditiselegans AT schuskekimr aneuronalacetylcholinereceptorregulatesthebalanceofmuscleexcitationandinhibitionincaenorhabditiselegans AT bessereaujeanlouis aneuronalacetylcholinereceptorregulatesthebalanceofmuscleexcitationandinhibitionincaenorhabditiselegans AT jorgensenerikm aneuronalacetylcholinereceptorregulatesthebalanceofmuscleexcitationandinhibitionincaenorhabditiselegans AT jinyishi aneuronalacetylcholinereceptorregulatesthebalanceofmuscleexcitationandinhibitionincaenorhabditiselegans AT horvitzhowardrobert aneuronalacetylcholinereceptorregulatesthebalanceofmuscleexcitationandinhibitionincaenorhabditiselegans AT jospinmaelle neuronalacetylcholinereceptorregulatesthebalanceofmuscleexcitationandinhibitionincaenorhabditiselegans AT qiyingchuanb neuronalacetylcholinereceptorregulatesthebalanceofmuscleexcitationandinhibitionincaenorhabditiselegans AT stawickitamaram neuronalacetylcholinereceptorregulatesthebalanceofmuscleexcitationandinhibitionincaenorhabditiselegans AT boulinthomas neuronalacetylcholinereceptorregulatesthebalanceofmuscleexcitationandinhibitionincaenorhabditiselegans AT schuskekimr neuronalacetylcholinereceptorregulatesthebalanceofmuscleexcitationandinhibitionincaenorhabditiselegans AT bessereaujeanlouis neuronalacetylcholinereceptorregulatesthebalanceofmuscleexcitationandinhibitionincaenorhabditiselegans AT jorgensenerikm neuronalacetylcholinereceptorregulatesthebalanceofmuscleexcitationandinhibitionincaenorhabditiselegans AT jinyishi neuronalacetylcholinereceptorregulatesthebalanceofmuscleexcitationandinhibitionincaenorhabditiselegans AT horvitzhowardrobert neuronalacetylcholinereceptorregulatesthebalanceofmuscleexcitationandinhibitionincaenorhabditiselegans |