Productive and non-productive binding of botulinum neurotoxin A to motor nerve endings are distinguished by its heavy chain
Botulinum neurotoxin type A, a di‐chain protein produced by Clostridium botulinum and responsible for botulism, blocks acetylcholine release from peripheral nerves by binding to the terminals, undergoing internalization and proteolyzing a protein essential for exocytosis. As botulinum neurotoxin is...
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description | Botulinum neurotoxin type A, a di‐chain protein produced by Clostridium botulinum and responsible for botulism, blocks acetylcholine release from peripheral nerves by binding to the terminals, undergoing internalization and proteolyzing a protein essential for exocytosis. As botulinum neurotoxin is being used clinically for the treatment of dystonias and certain spasticities, deciphering the details of its specific targeting to cholinergic nerve endings has assumed great importance. Thus, interaction of butolinum neurotoxin type A with murine motor nerve terminals—a prime target in vivo—was investigated. Autoradiographic analysis revealed saturable, high‐affinity interaction of radioiodinated toxin (0.4 nM) with two ecto‐acceptor types, distinguished by an excess of the toxin's heavy chain which prevented only a fraction of this binding. Botulinum neurotoxin was also biotinylated through its free sulfhydryl groups, known not to be essential for neurotoxicity. Similar binding of this active derivative was, likewise, partially blocked by heavy chain, confirming the above results. This binding that is resistant to heavy chain equates to botulinum neurotoxin interacting with productive ecto‐acceptors, leading to delivery to its cytosolic site of action, because heavy chain proved unable to antagonize toxin‐induced neuromuscular paralysis. In contrast, it is deduced that botulinum neurotoxin bound to heavy chain‐susceptible sites has a different fate, presumably due to trafficking via another route, and thus would be inefficient in causing neuroparalysis. © 1996 Wiley‐Liss, Inc. |
doi_str_mv | 10.1002/(SICI)1097-4547(19960501)44:3<263::AID-JNR7>3.0.CO;2-E |
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As botulinum neurotoxin is being used clinically for the treatment of dystonias and certain spasticities, deciphering the details of its specific targeting to cholinergic nerve endings has assumed great importance. Thus, interaction of butolinum neurotoxin type A with murine motor nerve terminals—a prime target in vivo—was investigated. Autoradiographic analysis revealed saturable, high‐affinity interaction of radioiodinated toxin (0.4 nM) with two ecto‐acceptor types, distinguished by an excess of the toxin's heavy chain which prevented only a fraction of this binding. Botulinum neurotoxin was also biotinylated through its free sulfhydryl groups, known not to be essential for neurotoxicity. Similar binding of this active derivative was, likewise, partially blocked by heavy chain, confirming the above results. This binding that is resistant to heavy chain equates to botulinum neurotoxin interacting with productive ecto‐acceptors, leading to delivery to its cytosolic site of action, because heavy chain proved unable to antagonize toxin‐induced neuromuscular paralysis. In contrast, it is deduced that botulinum neurotoxin bound to heavy chain‐susceptible sites has a different fate, presumably due to trafficking via another route, and thus would be inefficient in causing neuroparalysis. © 1996 Wiley‐Liss, Inc.</description><identifier>ISSN: 0360-4012</identifier><identifier>EISSN: 1097-4547</identifier><identifier>DOI: 10.1002/(SICI)1097-4547(19960501)44:3<263::AID-JNR7>3.0.CO;2-E</identifier><identifier>PMID: 8723765</identifier><language>eng</language><publisher>New York: John Wiley & Sons, Inc</publisher><subject>Animals ; Autoradiography ; Binding Sites ; Biotin ; biotinylated or iodinated botulinum neurotoxin A ; Botulinum Toxins - chemistry ; Botulinum Toxins - metabolism ; Botulinum Toxins - toxicity ; Clostridium botulinum ; dystonias ; Iodine Radioisotopes ; Mice ; Motor Endplate - drug effects ; Motor Endplate - metabolism ; Motor Neurons - metabolism ; neuromuscular junction ; Neuromuscular Junction - drug effects ; Paralysis - chemically induced ; spasticities</subject><ispartof>Journal of neuroscience research, 1996-05, Vol.44 (3), p.263-271</ispartof><rights>Copyright © 1996 Wiley‐Liss, Inc.</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><cites>FETCH-LOGICAL-c4337-dcbdbc6f00657d305d1d6547835b252e724515a65426070e80e14f61c17b30243</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://onlinelibrary.wiley.com/doi/pdf/10.1002%2F%28SICI%291097-4547%2819960501%2944%3A3%3C263%3A%3AAID-JNR7%3E3.0.CO%3B2-E$$EPDF$$P50$$Gwiley$$H</linktopdf><linktohtml>$$Uhttps://onlinelibrary.wiley.com/doi/full/10.1002%2F%28SICI%291097-4547%2819960501%2944%3A3%3C263%3A%3AAID-JNR7%3E3.0.CO%3B2-E$$EHTML$$P50$$Gwiley$$H</linktohtml><link.rule.ids>314,780,784,1417,27924,27925,45574,45575</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/8723765$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Daniels-Holgate, P.U.</creatorcontrib><creatorcontrib>Dolly, J.O.</creatorcontrib><title>Productive and non-productive binding of botulinum neurotoxin A to motor nerve endings are distinguished by its heavy chain</title><title>Journal of neuroscience research</title><addtitle>J. Neurosci. Res</addtitle><description>Botulinum neurotoxin type A, a di‐chain protein produced by Clostridium botulinum and responsible for botulism, blocks acetylcholine release from peripheral nerves by binding to the terminals, undergoing internalization and proteolyzing a protein essential for exocytosis. As botulinum neurotoxin is being used clinically for the treatment of dystonias and certain spasticities, deciphering the details of its specific targeting to cholinergic nerve endings has assumed great importance. Thus, interaction of butolinum neurotoxin type A with murine motor nerve terminals—a prime target in vivo—was investigated. Autoradiographic analysis revealed saturable, high‐affinity interaction of radioiodinated toxin (0.4 nM) with two ecto‐acceptor types, distinguished by an excess of the toxin's heavy chain which prevented only a fraction of this binding. Botulinum neurotoxin was also biotinylated through its free sulfhydryl groups, known not to be essential for neurotoxicity. Similar binding of this active derivative was, likewise, partially blocked by heavy chain, confirming the above results. This binding that is resistant to heavy chain equates to botulinum neurotoxin interacting with productive ecto‐acceptors, leading to delivery to its cytosolic site of action, because heavy chain proved unable to antagonize toxin‐induced neuromuscular paralysis. In contrast, it is deduced that botulinum neurotoxin bound to heavy chain‐susceptible sites has a different fate, presumably due to trafficking via another route, and thus would be inefficient in causing neuroparalysis. © 1996 Wiley‐Liss, Inc.</description><subject>Animals</subject><subject>Autoradiography</subject><subject>Binding Sites</subject><subject>Biotin</subject><subject>biotinylated or iodinated botulinum neurotoxin A</subject><subject>Botulinum Toxins - chemistry</subject><subject>Botulinum Toxins - metabolism</subject><subject>Botulinum Toxins - toxicity</subject><subject>Clostridium botulinum</subject><subject>dystonias</subject><subject>Iodine Radioisotopes</subject><subject>Mice</subject><subject>Motor Endplate - drug effects</subject><subject>Motor Endplate - metabolism</subject><subject>Motor Neurons - metabolism</subject><subject>neuromuscular junction</subject><subject>Neuromuscular Junction - drug effects</subject><subject>Paralysis - chemically induced</subject><subject>spasticities</subject><issn>0360-4012</issn><issn>1097-4547</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>1996</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqFkVtv00AQhS0EKqHwE5D2CbUPDrM3bxyqSpGblqAoodzVl5Ht3ZAFX4rXLo3486ybkD6AxNPqjGbO2ZkvCE4pDCkAe3n0fpbMjinEKhRSqCMaxxFIoMdCjPkJi_h4PJmdhW8W79QpH8IwWb5i4fRBMNiPPAwGwCMIBVD2OHji3DcAiGPJD4KDkWJcRXIQ_Hrb1LrLW3tjSFppUtVVeH1fymylbfWV1CuS1W1X2KorSWW6pm7rW1uRCWlrUnrR-GrjB8xdvyNpY4i2rvWis25tNMk2xLaOrE16syH5OrXV0-DRKi2cebZ7D4OP59MPyetwvryYJZN5mAvOVajzTGd5tAKIpNIcpKY68vuNuMyYZEYxIalMfYlFoMCMwFCximhOVcaBCX4YvNj6-sV-dMa1WFqXm6JIK1N3DqmMBROx8o2fto15UzvXmBVeN7ZMmw1SwJ4KYk8F-xNjf2L8QwWFQI6eCqKngj0VrwGTJTKceuPnux90WWn03naH4T74py3M5q_U_4b-I_NOe-Nwa-xRmNu9cdp8x0hxJfHz4gIvrxZf4Epc4pz_Bt4FuCc</recordid><startdate>19960501</startdate><enddate>19960501</enddate><creator>Daniels-Holgate, P.U.</creator><creator>Dolly, J.O.</creator><general>John Wiley & Sons, Inc</general><scope>BSCLL</scope><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7TK</scope></search><sort><creationdate>19960501</creationdate><title>Productive and non-productive binding of botulinum neurotoxin A to motor nerve endings are distinguished by its heavy chain</title><author>Daniels-Holgate, P.U. ; Dolly, J.O.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c4337-dcbdbc6f00657d305d1d6547835b252e724515a65426070e80e14f61c17b30243</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>1996</creationdate><topic>Animals</topic><topic>Autoradiography</topic><topic>Binding Sites</topic><topic>Biotin</topic><topic>biotinylated or iodinated botulinum neurotoxin A</topic><topic>Botulinum Toxins - chemistry</topic><topic>Botulinum Toxins - metabolism</topic><topic>Botulinum Toxins - toxicity</topic><topic>Clostridium botulinum</topic><topic>dystonias</topic><topic>Iodine Radioisotopes</topic><topic>Mice</topic><topic>Motor Endplate - drug effects</topic><topic>Motor Endplate - metabolism</topic><topic>Motor Neurons - metabolism</topic><topic>neuromuscular junction</topic><topic>Neuromuscular Junction - drug effects</topic><topic>Paralysis - chemically induced</topic><topic>spasticities</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Daniels-Holgate, P.U.</creatorcontrib><creatorcontrib>Dolly, J.O.</creatorcontrib><collection>Istex</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Neurosciences Abstracts</collection><jtitle>Journal of neuroscience research</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Daniels-Holgate, P.U.</au><au>Dolly, J.O.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Productive and non-productive binding of botulinum neurotoxin A to motor nerve endings are distinguished by its heavy chain</atitle><jtitle>Journal of neuroscience research</jtitle><addtitle>J. Neurosci. Res</addtitle><date>1996-05-01</date><risdate>1996</risdate><volume>44</volume><issue>3</issue><spage>263</spage><epage>271</epage><pages>263-271</pages><issn>0360-4012</issn><eissn>1097-4547</eissn><abstract>Botulinum neurotoxin type A, a di‐chain protein produced by Clostridium botulinum and responsible for botulism, blocks acetylcholine release from peripheral nerves by binding to the terminals, undergoing internalization and proteolyzing a protein essential for exocytosis. As botulinum neurotoxin is being used clinically for the treatment of dystonias and certain spasticities, deciphering the details of its specific targeting to cholinergic nerve endings has assumed great importance. Thus, interaction of butolinum neurotoxin type A with murine motor nerve terminals—a prime target in vivo—was investigated. Autoradiographic analysis revealed saturable, high‐affinity interaction of radioiodinated toxin (0.4 nM) with two ecto‐acceptor types, distinguished by an excess of the toxin's heavy chain which prevented only a fraction of this binding. Botulinum neurotoxin was also biotinylated through its free sulfhydryl groups, known not to be essential for neurotoxicity. Similar binding of this active derivative was, likewise, partially blocked by heavy chain, confirming the above results. This binding that is resistant to heavy chain equates to botulinum neurotoxin interacting with productive ecto‐acceptors, leading to delivery to its cytosolic site of action, because heavy chain proved unable to antagonize toxin‐induced neuromuscular paralysis. In contrast, it is deduced that botulinum neurotoxin bound to heavy chain‐susceptible sites has a different fate, presumably due to trafficking via another route, and thus would be inefficient in causing neuroparalysis. © 1996 Wiley‐Liss, Inc.</abstract><cop>New York</cop><pub>John Wiley & Sons, Inc</pub><pmid>8723765</pmid><doi>10.1002/(SICI)1097-4547(19960501)44:3<263::AID-JNR7>3.0.CO;2-E</doi><tpages>9</tpages></addata></record> |
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subjects | Animals Autoradiography Binding Sites Biotin biotinylated or iodinated botulinum neurotoxin A Botulinum Toxins - chemistry Botulinum Toxins - metabolism Botulinum Toxins - toxicity Clostridium botulinum dystonias Iodine Radioisotopes Mice Motor Endplate - drug effects Motor Endplate - metabolism Motor Neurons - metabolism neuromuscular junction Neuromuscular Junction - drug effects Paralysis - chemically induced spasticities |
title | Productive and non-productive binding of botulinum neurotoxin A to motor nerve endings are distinguished by its heavy chain |
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