Persistent activation of α7 nicotinic ACh receptors associated with stable induction of different desensitized states
Background and Purpose GAT107 ((3aR,4S,9bS)‐4‐(4‐bromo‐phenyl)‐3a,4,5,9b‐tetrahydro‐3H‐cyclopenta‐[c]quinoline‐8‐sulfonamide) is a positive allosteric modulator (PAM) and agonist of α7 nicotinic acetylcholine receptors (nAChRs)that can cause a prolonged period of primed potentiation of acetylcholine...
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| Veröffentlicht in: | British journal of pharmacology 2018-06, Vol.175 (11), p.1838-1854 |
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| creator | Papke, Roger L Stokes, Clare Damaj, M Imad Thakur, Ganesh A Manther, Khan Treinin, Millet Bagdas, Deniz Kulkarni, Abhijit R Horenstein, Nicole A |
| description | Background and Purpose
GAT107 ((3aR,4S,9bS)‐4‐(4‐bromo‐phenyl)‐3a,4,5,9b‐tetrahydro‐3H‐cyclopenta‐[c]quinoline‐8‐sulfonamide) is a positive allosteric modulator (PAM) and agonist of α7 nicotinic acetylcholine receptors (nAChRs)that can cause a prolonged period of primed potentiation of acetylcholine responses after drug washout. NS6740 is a silent agonist of α7 nAChRs that has little or no efficacy for activating the ion channel but induces stable desensitization states, some of which can be converted into channel‐active states by PAMs. Although GAT107 and NS6740 appear to stably induce different non‐conducting states, both agents are effective treatment for inflammation and inflammatory pain models. We sought to better understand how both of these drugs that have opposite effects on channel activation could regulate signal transduction.
Experimental Approach
Voltage‐clamp experiments were conducted with α7 nAChRs expressed in Xenopus oocytes.
Key Results
Long‐lived sensitivity to a PAM or to an agonist was produced by NS6740 or GAT107 respectively. With sequential applications, these two drugs induced varying levels of persistent activation, which is a unique condition for a receptor that is known for rapid desensitization. The non‐conducting states induced by NS6740 or GAT107 differ in their sensitivity to an α7 nAChR‐selective antagonist and in how effectively they promote current.
Conclusions & Implications
Our data suggest that the persistent currents represent a dynamic interconversion between different stable desensitized states and the PAM‐inducible conducting states. However, the similarity of NS6740 and GAT107 effects on inflammation and pain suggests that the different stable non‐conducting states have common activity on signal transduction.
Linked Articles
This article is part of a themed section on Nicotinic Acetylcholine Receptors. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v175.11/issuetoc |
| doi_str_mv | 10.1111/bph.13851 |
| format | Article |
| fullrecord | <record><control><sourceid>proquest_pubme</sourceid><recordid>TN_cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_5979752</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><sourcerecordid>2047350658</sourcerecordid><originalsourceid>FETCH-LOGICAL-c3581-8a96323b80eb02458debab779df0a7b151f9d53dc5f395366d8aae5463dc950e3</originalsourceid><addsrcrecordid>eNp1kctOAyEUhonR2HpZ-AKGxJWLURjKwGxMtPGWmOhC14SBMxbTDhVom_pWvojPJFo1upAFEM53Pk7yI7RHyRHN67iZjo4ok5yuoT4diKrgTNJ11CeEiIJSKXtoK8YnQnJR8E3UK2W-MFn10fwOQnQxQZewNsnNdXK-w77Fb68Cd8745PKOT4cjHMDANPkQsY7RG6cTWLxwaYRj0s0YsOvszHz3W9e2ED68FiJ00SX3kvmMJog7aKPV4wi7X-c2erg4vx9eFTe3l9fD05vCMC5pIXVdsZI1kkBDygGXFhrdCFHblmjRUE7b2nJmDW9ZzVlVWak18EGVn2pOgG2jk5V3OmsmYE0eJ-ixmgY30WGpvHbqb6VzI_Xo54rXoha8zIKDL0HwzzOIST35WejyzKokA8E4qbjM1OGKMsHHGKD9-YES9RGRyhGpz4gyu_97pB_yO5MMHK-AhRvD8n-TOru7WinfAfupnxY</addsrcrecordid><sourcetype>Open Access Repository</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype><pqid>2047350658</pqid></control><display><type>article</type><title>Persistent activation of α7 nicotinic ACh receptors associated with stable induction of different desensitized states</title><source>MEDLINE</source><source>Wiley Online Library Free Content</source><source>Access via Wiley Online Library</source><source>EZB-FREE-00999 freely available EZB journals</source><source>PubMed Central</source><source>Alma/SFX Local Collection</source><creator>Papke, Roger L ; Stokes, Clare ; Damaj, M Imad ; Thakur, Ganesh A ; Manther, Khan ; Treinin, Millet ; Bagdas, Deniz ; Kulkarni, Abhijit R ; Horenstein, Nicole A</creator><creatorcontrib>Papke, Roger L ; Stokes, Clare ; Damaj, M Imad ; Thakur, Ganesh A ; Manther, Khan ; Treinin, Millet ; Bagdas, Deniz ; Kulkarni, Abhijit R ; Horenstein, Nicole A</creatorcontrib><description>Background and Purpose
GAT107 ((3aR,4S,9bS)‐4‐(4‐bromo‐phenyl)‐3a,4,5,9b‐tetrahydro‐3H‐cyclopenta‐[c]quinoline‐8‐sulfonamide) is a positive allosteric modulator (PAM) and agonist of α7 nicotinic acetylcholine receptors (nAChRs)that can cause a prolonged period of primed potentiation of acetylcholine responses after drug washout. NS6740 is a silent agonist of α7 nAChRs that has little or no efficacy for activating the ion channel but induces stable desensitization states, some of which can be converted into channel‐active states by PAMs. Although GAT107 and NS6740 appear to stably induce different non‐conducting states, both agents are effective treatment for inflammation and inflammatory pain models. We sought to better understand how both of these drugs that have opposite effects on channel activation could regulate signal transduction.
Experimental Approach
Voltage‐clamp experiments were conducted with α7 nAChRs expressed in Xenopus oocytes.
Key Results
Long‐lived sensitivity to a PAM or to an agonist was produced by NS6740 or GAT107 respectively. With sequential applications, these two drugs induced varying levels of persistent activation, which is a unique condition for a receptor that is known for rapid desensitization. The non‐conducting states induced by NS6740 or GAT107 differ in their sensitivity to an α7 nAChR‐selective antagonist and in how effectively they promote current.
Conclusions & Implications
Our data suggest that the persistent currents represent a dynamic interconversion between different stable desensitized states and the PAM‐inducible conducting states. However, the similarity of NS6740 and GAT107 effects on inflammation and pain suggests that the different stable non‐conducting states have common activity on signal transduction.
Linked Articles
This article is part of a themed section on Nicotinic Acetylcholine Receptors. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v175.11/issuetoc</description><identifier>ISSN: 0007-1188</identifier><identifier>EISSN: 1476-5381</identifier><identifier>DOI: 10.1111/bph.13851</identifier><identifier>PMID: 28477386</identifier><language>eng</language><publisher>England: Blackwell Publishing Ltd</publisher><subject>Acetylcholine ; Acetylcholine receptors (nicotinic) ; Activation ; Allosteric properties ; Allosteric Regulation - drug effects ; alpha7 Nicotinic Acetylcholine Receptor - agonists ; alpha7 Nicotinic Acetylcholine Receptor - metabolism ; Animals ; Azabicyclo Compounds - pharmacology ; Desensitization ; Female ; Furans - pharmacology ; Inflammation ; Oocytes ; Pain ; Quinoline ; Quinolines - pharmacology ; Research Paper ; Sensitivity ; Signal transduction ; Sulfonamides ; Sulfonamides - pharmacology ; Themed Section: Research Papers ; Transduction ; Xenopus laevis</subject><ispartof>British journal of pharmacology, 2018-06, Vol.175 (11), p.1838-1854</ispartof><rights>2017 The British Pharmacological Society</rights><rights>2017 The British Pharmacological Society.</rights><rights>2018 The British Pharmacological Society</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c3581-8a96323b80eb02458debab779df0a7b151f9d53dc5f395366d8aae5463dc950e3</citedby><cites>FETCH-LOGICAL-c3581-8a96323b80eb02458debab779df0a7b151f9d53dc5f395366d8aae5463dc950e3</cites><orcidid>0000-0002-2625-2850 ; 0000-0001-7505-1230 ; 0000-0002-4468-8658</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC5979752/pdf/$$EPDF$$P50$$Gpubmedcentral$$H</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC5979752/$$EHTML$$P50$$Gpubmedcentral$$H</linktohtml><link.rule.ids>230,314,727,780,784,885,1417,1433,27924,27925,45574,45575,46409,46833,53791,53793</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/28477386$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Papke, Roger L</creatorcontrib><creatorcontrib>Stokes, Clare</creatorcontrib><creatorcontrib>Damaj, M Imad</creatorcontrib><creatorcontrib>Thakur, Ganesh A</creatorcontrib><creatorcontrib>Manther, Khan</creatorcontrib><creatorcontrib>Treinin, Millet</creatorcontrib><creatorcontrib>Bagdas, Deniz</creatorcontrib><creatorcontrib>Kulkarni, Abhijit R</creatorcontrib><creatorcontrib>Horenstein, Nicole A</creatorcontrib><title>Persistent activation of α7 nicotinic ACh receptors associated with stable induction of different desensitized states</title><title>British journal of pharmacology</title><addtitle>Br J Pharmacol</addtitle><description>Background and Purpose
GAT107 ((3aR,4S,9bS)‐4‐(4‐bromo‐phenyl)‐3a,4,5,9b‐tetrahydro‐3H‐cyclopenta‐[c]quinoline‐8‐sulfonamide) is a positive allosteric modulator (PAM) and agonist of α7 nicotinic acetylcholine receptors (nAChRs)that can cause a prolonged period of primed potentiation of acetylcholine responses after drug washout. NS6740 is a silent agonist of α7 nAChRs that has little or no efficacy for activating the ion channel but induces stable desensitization states, some of which can be converted into channel‐active states by PAMs. Although GAT107 and NS6740 appear to stably induce different non‐conducting states, both agents are effective treatment for inflammation and inflammatory pain models. We sought to better understand how both of these drugs that have opposite effects on channel activation could regulate signal transduction.
Experimental Approach
Voltage‐clamp experiments were conducted with α7 nAChRs expressed in Xenopus oocytes.
Key Results
Long‐lived sensitivity to a PAM or to an agonist was produced by NS6740 or GAT107 respectively. With sequential applications, these two drugs induced varying levels of persistent activation, which is a unique condition for a receptor that is known for rapid desensitization. The non‐conducting states induced by NS6740 or GAT107 differ in their sensitivity to an α7 nAChR‐selective antagonist and in how effectively they promote current.
Conclusions & Implications
Our data suggest that the persistent currents represent a dynamic interconversion between different stable desensitized states and the PAM‐inducible conducting states. However, the similarity of NS6740 and GAT107 effects on inflammation and pain suggests that the different stable non‐conducting states have common activity on signal transduction.
Linked Articles
This article is part of a themed section on Nicotinic Acetylcholine Receptors. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v175.11/issuetoc</description><subject>Acetylcholine</subject><subject>Acetylcholine receptors (nicotinic)</subject><subject>Activation</subject><subject>Allosteric properties</subject><subject>Allosteric Regulation - drug effects</subject><subject>alpha7 Nicotinic Acetylcholine Receptor - agonists</subject><subject>alpha7 Nicotinic Acetylcholine Receptor - metabolism</subject><subject>Animals</subject><subject>Azabicyclo Compounds - pharmacology</subject><subject>Desensitization</subject><subject>Female</subject><subject>Furans - pharmacology</subject><subject>Inflammation</subject><subject>Oocytes</subject><subject>Pain</subject><subject>Quinoline</subject><subject>Quinolines - pharmacology</subject><subject>Research Paper</subject><subject>Sensitivity</subject><subject>Signal transduction</subject><subject>Sulfonamides</subject><subject>Sulfonamides - pharmacology</subject><subject>Themed Section: Research Papers</subject><subject>Transduction</subject><subject>Xenopus laevis</subject><issn>0007-1188</issn><issn>1476-5381</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2018</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp1kctOAyEUhonR2HpZ-AKGxJWLURjKwGxMtPGWmOhC14SBMxbTDhVom_pWvojPJFo1upAFEM53Pk7yI7RHyRHN67iZjo4ok5yuoT4diKrgTNJ11CeEiIJSKXtoK8YnQnJR8E3UK2W-MFn10fwOQnQxQZewNsnNdXK-w77Fb68Cd8745PKOT4cjHMDANPkQsY7RG6cTWLxwaYRj0s0YsOvszHz3W9e2ED68FiJ00SX3kvmMJog7aKPV4wi7X-c2erg4vx9eFTe3l9fD05vCMC5pIXVdsZI1kkBDygGXFhrdCFHblmjRUE7b2nJmDW9ZzVlVWak18EGVn2pOgG2jk5V3OmsmYE0eJ-ixmgY30WGpvHbqb6VzI_Xo54rXoha8zIKDL0HwzzOIST35WejyzKokA8E4qbjM1OGKMsHHGKD9-YES9RGRyhGpz4gyu_97pB_yO5MMHK-AhRvD8n-TOru7WinfAfupnxY</recordid><startdate>201806</startdate><enddate>201806</enddate><creator>Papke, Roger L</creator><creator>Stokes, Clare</creator><creator>Damaj, M Imad</creator><creator>Thakur, Ganesh A</creator><creator>Manther, Khan</creator><creator>Treinin, Millet</creator><creator>Bagdas, Deniz</creator><creator>Kulkarni, Abhijit R</creator><creator>Horenstein, Nicole A</creator><general>Blackwell Publishing Ltd</general><general>John Wiley and Sons Inc</general><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>7QP</scope><scope>7TK</scope><scope>K9.</scope><scope>NAPCQ</scope><scope>5PM</scope><orcidid>https://orcid.org/0000-0002-2625-2850</orcidid><orcidid>https://orcid.org/0000-0001-7505-1230</orcidid><orcidid>https://orcid.org/0000-0002-4468-8658</orcidid></search><sort><creationdate>201806</creationdate><title>Persistent activation of α7 nicotinic ACh receptors associated with stable induction of different desensitized states</title><author>Papke, Roger L ; Stokes, Clare ; Damaj, M Imad ; Thakur, Ganesh A ; Manther, Khan ; Treinin, Millet ; Bagdas, Deniz ; Kulkarni, Abhijit R ; Horenstein, Nicole A</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c3581-8a96323b80eb02458debab779df0a7b151f9d53dc5f395366d8aae5463dc950e3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2018</creationdate><topic>Acetylcholine</topic><topic>Acetylcholine receptors (nicotinic)</topic><topic>Activation</topic><topic>Allosteric properties</topic><topic>Allosteric Regulation - drug effects</topic><topic>alpha7 Nicotinic Acetylcholine Receptor - agonists</topic><topic>alpha7 Nicotinic Acetylcholine Receptor - metabolism</topic><topic>Animals</topic><topic>Azabicyclo Compounds - pharmacology</topic><topic>Desensitization</topic><topic>Female</topic><topic>Furans - pharmacology</topic><topic>Inflammation</topic><topic>Oocytes</topic><topic>Pain</topic><topic>Quinoline</topic><topic>Quinolines - pharmacology</topic><topic>Research Paper</topic><topic>Sensitivity</topic><topic>Signal transduction</topic><topic>Sulfonamides</topic><topic>Sulfonamides - pharmacology</topic><topic>Themed Section: Research Papers</topic><topic>Transduction</topic><topic>Xenopus laevis</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Papke, Roger L</creatorcontrib><creatorcontrib>Stokes, Clare</creatorcontrib><creatorcontrib>Damaj, M Imad</creatorcontrib><creatorcontrib>Thakur, Ganesh A</creatorcontrib><creatorcontrib>Manther, Khan</creatorcontrib><creatorcontrib>Treinin, Millet</creatorcontrib><creatorcontrib>Bagdas, Deniz</creatorcontrib><creatorcontrib>Kulkarni, Abhijit R</creatorcontrib><creatorcontrib>Horenstein, Nicole A</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Calcium & Calcified Tissue Abstracts</collection><collection>Neurosciences Abstracts</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>Nursing & Allied Health Premium</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>British journal of pharmacology</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Papke, Roger L</au><au>Stokes, Clare</au><au>Damaj, M Imad</au><au>Thakur, Ganesh A</au><au>Manther, Khan</au><au>Treinin, Millet</au><au>Bagdas, Deniz</au><au>Kulkarni, Abhijit R</au><au>Horenstein, Nicole A</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Persistent activation of α7 nicotinic ACh receptors associated with stable induction of different desensitized states</atitle><jtitle>British journal of pharmacology</jtitle><addtitle>Br J Pharmacol</addtitle><date>2018-06</date><risdate>2018</risdate><volume>175</volume><issue>11</issue><spage>1838</spage><epage>1854</epage><pages>1838-1854</pages><issn>0007-1188</issn><eissn>1476-5381</eissn><abstract>Background and Purpose
GAT107 ((3aR,4S,9bS)‐4‐(4‐bromo‐phenyl)‐3a,4,5,9b‐tetrahydro‐3H‐cyclopenta‐[c]quinoline‐8‐sulfonamide) is a positive allosteric modulator (PAM) and agonist of α7 nicotinic acetylcholine receptors (nAChRs)that can cause a prolonged period of primed potentiation of acetylcholine responses after drug washout. NS6740 is a silent agonist of α7 nAChRs that has little or no efficacy for activating the ion channel but induces stable desensitization states, some of which can be converted into channel‐active states by PAMs. Although GAT107 and NS6740 appear to stably induce different non‐conducting states, both agents are effective treatment for inflammation and inflammatory pain models. We sought to better understand how both of these drugs that have opposite effects on channel activation could regulate signal transduction.
Experimental Approach
Voltage‐clamp experiments were conducted with α7 nAChRs expressed in Xenopus oocytes.
Key Results
Long‐lived sensitivity to a PAM or to an agonist was produced by NS6740 or GAT107 respectively. With sequential applications, these two drugs induced varying levels of persistent activation, which is a unique condition for a receptor that is known for rapid desensitization. The non‐conducting states induced by NS6740 or GAT107 differ in their sensitivity to an α7 nAChR‐selective antagonist and in how effectively they promote current.
Conclusions & Implications
Our data suggest that the persistent currents represent a dynamic interconversion between different stable desensitized states and the PAM‐inducible conducting states. However, the similarity of NS6740 and GAT107 effects on inflammation and pain suggests that the different stable non‐conducting states have common activity on signal transduction.
Linked Articles
This article is part of a themed section on Nicotinic Acetylcholine Receptors. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v175.11/issuetoc</abstract><cop>England</cop><pub>Blackwell Publishing Ltd</pub><pmid>28477386</pmid><doi>10.1111/bph.13851</doi><tpages>17</tpages><orcidid>https://orcid.org/0000-0002-2625-2850</orcidid><orcidid>https://orcid.org/0000-0001-7505-1230</orcidid><orcidid>https://orcid.org/0000-0002-4468-8658</orcidid><oa>free_for_read</oa></addata></record> |
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| source | MEDLINE; Wiley Online Library Free Content; Access via Wiley Online Library; EZB-FREE-00999 freely available EZB journals; PubMed Central; Alma/SFX Local Collection |
| subjects | Acetylcholine Acetylcholine receptors (nicotinic) Activation Allosteric properties Allosteric Regulation - drug effects alpha7 Nicotinic Acetylcholine Receptor - agonists alpha7 Nicotinic Acetylcholine Receptor - metabolism Animals Azabicyclo Compounds - pharmacology Desensitization Female Furans - pharmacology Inflammation Oocytes Pain Quinoline Quinolines - pharmacology Research Paper Sensitivity Signal transduction Sulfonamides Sulfonamides - pharmacology Themed Section: Research Papers Transduction Xenopus laevis |
| title | Persistent activation of α7 nicotinic ACh receptors associated with stable induction of different desensitized states |
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