Differential regulation of evoked and spontaneous neurotransmitter release by C-terminal modifications of complexin
Complexins are small α-helical proteins that modulate neurotransmitter release by binding to SNARE complexes during synaptic vesicle exocytosis. They have been found to function as fusion clamps to inhibit spontaneous synaptic vesicle fusion in the absence of Ca[superscript 2+], while also promoting...
| Main Authors: | , , , , , |
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| Format: | Article |
| Language: | en_US |
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Elsevier
2016
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| Online Access: | http://hdl.handle.net/1721.1/101273 https://orcid.org/0000-0001-5576-2887 |
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| author | Akbergenova, Yulia Huntwork-Rodriguez, Sarah Volfson, Dina Littleton, J. Troy Buhl, Lauren Kaye Jorquera, Ramon |
| author2 | Massachusetts Institute of Technology. Department of Biology |
| author_facet | Massachusetts Institute of Technology. Department of Biology Akbergenova, Yulia Huntwork-Rodriguez, Sarah Volfson, Dina Littleton, J. Troy Buhl, Lauren Kaye Jorquera, Ramon |
| author_sort | Akbergenova, Yulia |
| collection | MIT |
| description | Complexins are small α-helical proteins that modulate neurotransmitter release by binding to SNARE complexes during synaptic vesicle exocytosis. They have been found to function as fusion clamps to inhibit spontaneous synaptic vesicle fusion in the absence of Ca[superscript 2+], while also promoting evoked neurotransmitter release following an action potential. Complexins consist of an N-terminal domain and an accessory α-helix that regulates the activating and inhibitory properties of the protein, respectively, and a central α-helix that binds the SNARE complex and is essential for both functions. In addition, complexins contain a largely unstructured C-terminal domain whose role in synaptic vesicle cycling is poorly defined. Here, we demonstrate that the C-terminus of Drosophila complexin (DmCpx) regulates localization to synapses and that alternative splicing of the C-terminus can differentially regulate spontaneous and evoked neurotransmitter release. Characterization of the single DmCpx gene by mRNA analysis revealed expression of two alternatively expressed isoforms, DmCpx7A and DmCpx7B, which encode proteins with different C-termini that contain or lack a membrane tethering prenylation domain. The predominant isoform, DmCpx7A, is further modified by RNA editing within this C-terminal region. Functional analysis of the splice isoforms showed that both are similarly localized to synaptic boutons at larval neuromuscular junctions, but have differential effects on the regulation of evoked and spontaneous fusion. These data indicate that the C-terminus of Drosophila complexin regulates both spontaneous and evoked release through separate mechanisms and that alternative splicing generates isoforms with distinct effects on the two major modes of synaptic vesicle fusion at synapses. |
| first_indexed | 2024-09-23T11:58:20Z |
| format | Article |
| id | mit-1721.1/101273 |
| institution | Massachusetts Institute of Technology |
| language | en_US |
| last_indexed | 2024-09-23T11:58:20Z |
| publishDate | 2016 |
| publisher | Elsevier |
| record_format | dspace |
| spelling | mit-1721.1/1012732022-10-01T07:23:02Z Differential regulation of evoked and spontaneous neurotransmitter release by C-terminal modifications of complexin Akbergenova, Yulia Huntwork-Rodriguez, Sarah Volfson, Dina Littleton, J. Troy Buhl, Lauren Kaye Jorquera, Ramon Massachusetts Institute of Technology. Department of Biology Massachusetts Institute of Technology. Department of Brain and Cognitive Sciences Picower Institute for Learning and Memory Buhl, Lauren K. Jorquera, Ramon A. Akbergenova, Yulia Huntwork-Rodriguez, Sarah Volfson, Dina Littleton, J. Troy Complexins are small α-helical proteins that modulate neurotransmitter release by binding to SNARE complexes during synaptic vesicle exocytosis. They have been found to function as fusion clamps to inhibit spontaneous synaptic vesicle fusion in the absence of Ca[superscript 2+], while also promoting evoked neurotransmitter release following an action potential. Complexins consist of an N-terminal domain and an accessory α-helix that regulates the activating and inhibitory properties of the protein, respectively, and a central α-helix that binds the SNARE complex and is essential for both functions. In addition, complexins contain a largely unstructured C-terminal domain whose role in synaptic vesicle cycling is poorly defined. Here, we demonstrate that the C-terminus of Drosophila complexin (DmCpx) regulates localization to synapses and that alternative splicing of the C-terminus can differentially regulate spontaneous and evoked neurotransmitter release. Characterization of the single DmCpx gene by mRNA analysis revealed expression of two alternatively expressed isoforms, DmCpx7A and DmCpx7B, which encode proteins with different C-termini that contain or lack a membrane tethering prenylation domain. The predominant isoform, DmCpx7A, is further modified by RNA editing within this C-terminal region. Functional analysis of the splice isoforms showed that both are similarly localized to synaptic boutons at larval neuromuscular junctions, but have differential effects on the regulation of evoked and spontaneous fusion. These data indicate that the C-terminus of Drosophila complexin regulates both spontaneous and evoked release through separate mechanisms and that alternative splicing generates isoforms with distinct effects on the two major modes of synaptic vesicle fusion at synapses. Pew Charitable Trusts. Latin American Fellow Program in Biomedical Science National Institutes of Health (U.S.) (Grant NS40296) 2016-02-25T14:56:13Z 2016-02-25T14:56:13Z 2012-11 2012-09 Article http://purl.org/eprint/type/JournalArticle 10447431 1095-9327 http://hdl.handle.net/1721.1/101273 Buhl, Lauren K., Ramon A. Jorquera, Yulia Akbergenova, Sarah Huntwork-Rodriguez, Dina Volfson, and J. Troy Littleton. “Differential Regulation of Evoked and Spontaneous Neurotransmitter Release by C-Terminal Modifications of Complexin.” Molecular and Cellular Neuroscience 52 (January 2013): 161–172. https://orcid.org/0000-0001-5576-2887 en_US http://dx.doi.org/10.1016/j.mcn.2012.11.009 Molecular and Cellular Neuroscience Creative Commons Attribution-Noncommercial-NoDerivatives http://creativecommons.org/licenses/by-nc-nd/4.0/ application/pdf Elsevier PMC |
| spellingShingle | Akbergenova, Yulia Huntwork-Rodriguez, Sarah Volfson, Dina Littleton, J. Troy Buhl, Lauren Kaye Jorquera, Ramon Differential regulation of evoked and spontaneous neurotransmitter release by C-terminal modifications of complexin |
| title | Differential regulation of evoked and spontaneous neurotransmitter release by C-terminal modifications of complexin |
| title_full | Differential regulation of evoked and spontaneous neurotransmitter release by C-terminal modifications of complexin |
| title_fullStr | Differential regulation of evoked and spontaneous neurotransmitter release by C-terminal modifications of complexin |
| title_full_unstemmed | Differential regulation of evoked and spontaneous neurotransmitter release by C-terminal modifications of complexin |
| title_short | Differential regulation of evoked and spontaneous neurotransmitter release by C-terminal modifications of complexin |
| title_sort | differential regulation of evoked and spontaneous neurotransmitter release by c terminal modifications of complexin |
| url | http://hdl.handle.net/1721.1/101273 https://orcid.org/0000-0001-5576-2887 |
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