Loading…
Neural peptidase endothelin-converting enzyme 1 regulates endothelin 1-induced pruritus
In humans, pruritus (itch) is a common but poorly understood symptom in numerous skin and systemic diseases. Endothelin 1 (ET-1) evokes histamine-independent pruritus in mammals through activation of its cognate G protein-coupled receptor endothelin A receptor (ETAR). Here, we have identified neural...
Saved in:
| Published in: | The Journal of clinical investigation 2014-06, Vol.124 (6), p.2683-2695 |
|---|---|
| Main Authors: | , , , , , , , , , , , , , , , , , , |
| Format: | Article |
| Language: | English |
| Subjects: | |
| Citations: | Items that this one cites Items that cite this one |
| Online Access: | Get full text |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| cited_by | cdi_FETCH-LOGICAL-c5913-50917df6b5220ba4395bba6c201f5c683612464f3e52a9a4dcc9b3f3f6f99d0a3 |
|---|---|
| cites | cdi_FETCH-LOGICAL-c5913-50917df6b5220ba4395bba6c201f5c683612464f3e52a9a4dcc9b3f3f6f99d0a3 |
| container_end_page | 2695 |
| container_issue | 6 |
| container_start_page | 2683 |
| container_title | The Journal of clinical investigation |
| container_volume | 124 |
| creator | Kido-Nakahara, Makiko Buddenkotte, Jörg Kempkes, Cordula Ikoma, Akihiko Cevikbas, Ferda Akiyama, Tasuku Nunes, Frank Seeliger, Stephan Hasdemir, Burcu Mess, Christian Buhl, Timo Sulk, Mathias Müller, Frank-Ulrich Metze, Dieter Bunnett, Nigel W Bhargava, Aditi Carstens, Earl Furue, Masutaka Steinhoff, Martin |
| description | In humans, pruritus (itch) is a common but poorly understood symptom in numerous skin and systemic diseases. Endothelin 1 (ET-1) evokes histamine-independent pruritus in mammals through activation of its cognate G protein-coupled receptor endothelin A receptor (ETAR). Here, we have identified neural endothelin-converting enzyme 1 (ECE-1) as a key regulator of ET-1-induced pruritus and neural signaling of itch. We show here that ETAR, ET-1, and ECE-1 are expressed and colocalize in murine dorsal root ganglia (DRG) neurons and human skin nerves. In murine DRG neurons, ET-1 induced internalization of ETAR within ECE-1-containing endosomes. ECE-1 inhibition slowed ETAR recycling yet prolonged ET-1-induced activation of ERK1/2, but not p38. In a murine itch model, ET-1-induced scratching behavior was substantially augmented by pharmacological ECE-1 inhibition and abrogated by treatment with an ERK1/2 inhibitor. Using iontophoresis, we demonstrated that ET-1 is a potent, partially histamine-independent pruritogen in humans. Immunohistochemical evaluation of skin from prurigo nodularis patients confirmed an upregulation of the ET-1/ETAR/ECE-1/ERK1/2 axis in patients with chronic itch. Together, our data identify the neural peptidase ECE-1 as a negative regulator of itch on sensory nerves by directly regulating ET-1-induced pruritus in humans and mice. Furthermore, these results implicate the ET-1/ECE-1/ERK1/2 pathway as a therapeutic target to treat pruritus in humans. |
| doi_str_mv | 10.1172/JCI67323 |
| format | article |
| fullrecord | <record><control><sourceid>gale_pubme</sourceid><recordid>TN_cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_4038561</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><galeid>A372250832</galeid><sourcerecordid>A372250832</sourcerecordid><originalsourceid>FETCH-LOGICAL-c5913-50917df6b5220ba4395bba6c201f5c683612464f3e52a9a4dcc9b3f3f6f99d0a3</originalsourceid><addsrcrecordid>eNqN0luLEzEUAOBBFLdWwV8gA4Low6y5z-RFWIqXyuKC18eQyZyZZpkmNcksrr_eFLtrK31Y8hA4-c4hyTlF8RSjU4xr8vrjYilqSui9YoY5b6qG0OZ-MUOI4ErWtDkpHsV4iRBmjLOHxQlhDSZC8Fnx4xNMQY_lBjbJdjpCCa7zaQWjdZXx7gpCsm7I0d_XayhxGWCYRp0g7sESV9Z1k4Gu3IQp2DTFx8WDXo8Rnuz2efHt3duviw_V-cX75eLsvDJcYlpxJHHd9aLlhKBWMyp522phCMI9N6KhAhMmWE-BEy0164yRLe1pL3opO6TpvHjzt-5matfQGXApP0dtgl3rcK28turwxNmVGvyVYog2XOBc4OWuQPA_J4hJrW00MI7agZ-iwpwxhGvB6B0oJZJJJrb0-X_00k_B5Z_YKknqWgjxTw16BGVd7_MVzbaoOqM1IRw1uanzojqiBnCQ3-Md9DaHD_zpEZ9XB2trjia8OkjIJsGvNOgpRrX88vnu9uL7oX2xZ1egx7SKfpyS9S4ewt3HmuBjDNDf9g8jtR1wdTPgmT7b7_ctvJlo-gd1VvDE</addsrcrecordid><sourcetype>Open Access Repository</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype><pqid>1539277666</pqid></control><display><type>article</type><title>Neural peptidase endothelin-converting enzyme 1 regulates endothelin 1-induced pruritus</title><source>PubMed Central</source><source>EZB Electronic Journals Library</source><creator>Kido-Nakahara, Makiko ; Buddenkotte, Jörg ; Kempkes, Cordula ; Ikoma, Akihiko ; Cevikbas, Ferda ; Akiyama, Tasuku ; Nunes, Frank ; Seeliger, Stephan ; Hasdemir, Burcu ; Mess, Christian ; Buhl, Timo ; Sulk, Mathias ; Müller, Frank-Ulrich ; Metze, Dieter ; Bunnett, Nigel W ; Bhargava, Aditi ; Carstens, Earl ; Furue, Masutaka ; Steinhoff, Martin</creator><creatorcontrib>Kido-Nakahara, Makiko ; Buddenkotte, Jörg ; Kempkes, Cordula ; Ikoma, Akihiko ; Cevikbas, Ferda ; Akiyama, Tasuku ; Nunes, Frank ; Seeliger, Stephan ; Hasdemir, Burcu ; Mess, Christian ; Buhl, Timo ; Sulk, Mathias ; Müller, Frank-Ulrich ; Metze, Dieter ; Bunnett, Nigel W ; Bhargava, Aditi ; Carstens, Earl ; Furue, Masutaka ; Steinhoff, Martin</creatorcontrib><description>In humans, pruritus (itch) is a common but poorly understood symptom in numerous skin and systemic diseases. Endothelin 1 (ET-1) evokes histamine-independent pruritus in mammals through activation of its cognate G protein-coupled receptor endothelin A receptor (ETAR). Here, we have identified neural endothelin-converting enzyme 1 (ECE-1) as a key regulator of ET-1-induced pruritus and neural signaling of itch. We show here that ETAR, ET-1, and ECE-1 are expressed and colocalize in murine dorsal root ganglia (DRG) neurons and human skin nerves. In murine DRG neurons, ET-1 induced internalization of ETAR within ECE-1-containing endosomes. ECE-1 inhibition slowed ETAR recycling yet prolonged ET-1-induced activation of ERK1/2, but not p38. In a murine itch model, ET-1-induced scratching behavior was substantially augmented by pharmacological ECE-1 inhibition and abrogated by treatment with an ERK1/2 inhibitor. Using iontophoresis, we demonstrated that ET-1 is a potent, partially histamine-independent pruritogen in humans. Immunohistochemical evaluation of skin from prurigo nodularis patients confirmed an upregulation of the ET-1/ETAR/ECE-1/ERK1/2 axis in patients with chronic itch. Together, our data identify the neural peptidase ECE-1 as a negative regulator of itch on sensory nerves by directly regulating ET-1-induced pruritus in humans and mice. Furthermore, these results implicate the ET-1/ECE-1/ERK1/2 pathway as a therapeutic target to treat pruritus in humans.</description><identifier>ISSN: 0021-9738</identifier><identifier>EISSN: 1558-8238</identifier><identifier>DOI: 10.1172/JCI67323</identifier><identifier>PMID: 24812665</identifier><language>eng</language><publisher>United States: American Society for Clinical Investigation</publisher><subject>Adult ; Age ; Animals ; Aspartic Acid Endopeptidases - antagonists & inhibitors ; Aspartic Acid Endopeptidases - genetics ; Aspartic Acid Endopeptidases - metabolism ; Autoimmune diseases ; Biomedical research ; Cellular signal transduction ; Endothelin-1 - administration & dosage ; Endothelin-1 - genetics ; Endothelin-1 - metabolism ; Endothelin-Converting Enzymes ; Enzymes ; Female ; Ganglia, Spinal - metabolism ; Health aspects ; Humans ; Kinases ; Laboratory animals ; Male ; MAP Kinase Signaling System ; Metalloendopeptidases - antagonists & inhibitors ; Metalloendopeptidases - genetics ; Metalloendopeptidases - metabolism ; Mice ; Mice, Inbred C57BL ; Mice, Knockout ; Nervous system ; Neurons ; Neuropeptides ; Pain ; Physiological aspects ; Proteases ; Pruritus ; Pruritus - etiology ; Pruritus - genetics ; Pruritus - metabolism ; Receptor, Endothelin A - metabolism ; Recycling ; Signal Transduction ; Skin - innervation ; Skin - metabolism ; Skin - pathology ; Software ; Up-Regulation</subject><ispartof>The Journal of clinical investigation, 2014-06, Vol.124 (6), p.2683-2695</ispartof><rights>COPYRIGHT 2014 American Society for Clinical Investigation</rights><rights>Copyright American Society for Clinical Investigation Jun 2014</rights><rights>Copyright © 2014, American Society for Clinical Investigation 2014</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c5913-50917df6b5220ba4395bba6c201f5c683612464f3e52a9a4dcc9b3f3f6f99d0a3</citedby><cites>FETCH-LOGICAL-c5913-50917df6b5220ba4395bba6c201f5c683612464f3e52a9a4dcc9b3f3f6f99d0a3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC4038561/pdf/$$EPDF$$P50$$Gpubmedcentral$$H</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC4038561/$$EHTML$$P50$$Gpubmedcentral$$H</linktohtml><link.rule.ids>230,315,733,786,790,891,27957,27958,53827,53829</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/24812665$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Kido-Nakahara, Makiko</creatorcontrib><creatorcontrib>Buddenkotte, Jörg</creatorcontrib><creatorcontrib>Kempkes, Cordula</creatorcontrib><creatorcontrib>Ikoma, Akihiko</creatorcontrib><creatorcontrib>Cevikbas, Ferda</creatorcontrib><creatorcontrib>Akiyama, Tasuku</creatorcontrib><creatorcontrib>Nunes, Frank</creatorcontrib><creatorcontrib>Seeliger, Stephan</creatorcontrib><creatorcontrib>Hasdemir, Burcu</creatorcontrib><creatorcontrib>Mess, Christian</creatorcontrib><creatorcontrib>Buhl, Timo</creatorcontrib><creatorcontrib>Sulk, Mathias</creatorcontrib><creatorcontrib>Müller, Frank-Ulrich</creatorcontrib><creatorcontrib>Metze, Dieter</creatorcontrib><creatorcontrib>Bunnett, Nigel W</creatorcontrib><creatorcontrib>Bhargava, Aditi</creatorcontrib><creatorcontrib>Carstens, Earl</creatorcontrib><creatorcontrib>Furue, Masutaka</creatorcontrib><creatorcontrib>Steinhoff, Martin</creatorcontrib><title>Neural peptidase endothelin-converting enzyme 1 regulates endothelin 1-induced pruritus</title><title>The Journal of clinical investigation</title><addtitle>J Clin Invest</addtitle><description>In humans, pruritus (itch) is a common but poorly understood symptom in numerous skin and systemic diseases. Endothelin 1 (ET-1) evokes histamine-independent pruritus in mammals through activation of its cognate G protein-coupled receptor endothelin A receptor (ETAR). Here, we have identified neural endothelin-converting enzyme 1 (ECE-1) as a key regulator of ET-1-induced pruritus and neural signaling of itch. We show here that ETAR, ET-1, and ECE-1 are expressed and colocalize in murine dorsal root ganglia (DRG) neurons and human skin nerves. In murine DRG neurons, ET-1 induced internalization of ETAR within ECE-1-containing endosomes. ECE-1 inhibition slowed ETAR recycling yet prolonged ET-1-induced activation of ERK1/2, but not p38. In a murine itch model, ET-1-induced scratching behavior was substantially augmented by pharmacological ECE-1 inhibition and abrogated by treatment with an ERK1/2 inhibitor. Using iontophoresis, we demonstrated that ET-1 is a potent, partially histamine-independent pruritogen in humans. Immunohistochemical evaluation of skin from prurigo nodularis patients confirmed an upregulation of the ET-1/ETAR/ECE-1/ERK1/2 axis in patients with chronic itch. Together, our data identify the neural peptidase ECE-1 as a negative regulator of itch on sensory nerves by directly regulating ET-1-induced pruritus in humans and mice. Furthermore, these results implicate the ET-1/ECE-1/ERK1/2 pathway as a therapeutic target to treat pruritus in humans.</description><subject>Adult</subject><subject>Age</subject><subject>Animals</subject><subject>Aspartic Acid Endopeptidases - antagonists & inhibitors</subject><subject>Aspartic Acid Endopeptidases - genetics</subject><subject>Aspartic Acid Endopeptidases - metabolism</subject><subject>Autoimmune diseases</subject><subject>Biomedical research</subject><subject>Cellular signal transduction</subject><subject>Endothelin-1 - administration & dosage</subject><subject>Endothelin-1 - genetics</subject><subject>Endothelin-1 - metabolism</subject><subject>Endothelin-Converting Enzymes</subject><subject>Enzymes</subject><subject>Female</subject><subject>Ganglia, Spinal - metabolism</subject><subject>Health aspects</subject><subject>Humans</subject><subject>Kinases</subject><subject>Laboratory animals</subject><subject>Male</subject><subject>MAP Kinase Signaling System</subject><subject>Metalloendopeptidases - antagonists & inhibitors</subject><subject>Metalloendopeptidases - genetics</subject><subject>Metalloendopeptidases - metabolism</subject><subject>Mice</subject><subject>Mice, Inbred C57BL</subject><subject>Mice, Knockout</subject><subject>Nervous system</subject><subject>Neurons</subject><subject>Neuropeptides</subject><subject>Pain</subject><subject>Physiological aspects</subject><subject>Proteases</subject><subject>Pruritus</subject><subject>Pruritus - etiology</subject><subject>Pruritus - genetics</subject><subject>Pruritus - metabolism</subject><subject>Receptor, Endothelin A - metabolism</subject><subject>Recycling</subject><subject>Signal Transduction</subject><subject>Skin - innervation</subject><subject>Skin - metabolism</subject><subject>Skin - pathology</subject><subject>Software</subject><subject>Up-Regulation</subject><issn>0021-9738</issn><issn>1558-8238</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2014</creationdate><recordtype>article</recordtype><recordid>eNqN0luLEzEUAOBBFLdWwV8gA4Low6y5z-RFWIqXyuKC18eQyZyZZpkmNcksrr_eFLtrK31Y8hA4-c4hyTlF8RSjU4xr8vrjYilqSui9YoY5b6qG0OZ-MUOI4ErWtDkpHsV4iRBmjLOHxQlhDSZC8Fnx4xNMQY_lBjbJdjpCCa7zaQWjdZXx7gpCsm7I0d_XayhxGWCYRp0g7sESV9Z1k4Gu3IQp2DTFx8WDXo8Rnuz2efHt3duviw_V-cX75eLsvDJcYlpxJHHd9aLlhKBWMyp522phCMI9N6KhAhMmWE-BEy0164yRLe1pL3opO6TpvHjzt-5matfQGXApP0dtgl3rcK28turwxNmVGvyVYog2XOBc4OWuQPA_J4hJrW00MI7agZ-iwpwxhGvB6B0oJZJJJrb0-X_00k_B5Z_YKknqWgjxTw16BGVd7_MVzbaoOqM1IRw1uanzojqiBnCQ3-Md9DaHD_zpEZ9XB2trjia8OkjIJsGvNOgpRrX88vnu9uL7oX2xZ1egx7SKfpyS9S4ewt3HmuBjDNDf9g8jtR1wdTPgmT7b7_ctvJlo-gd1VvDE</recordid><startdate>201406</startdate><enddate>201406</enddate><creator>Kido-Nakahara, Makiko</creator><creator>Buddenkotte, Jörg</creator><creator>Kempkes, Cordula</creator><creator>Ikoma, Akihiko</creator><creator>Cevikbas, Ferda</creator><creator>Akiyama, Tasuku</creator><creator>Nunes, Frank</creator><creator>Seeliger, Stephan</creator><creator>Hasdemir, Burcu</creator><creator>Mess, Christian</creator><creator>Buhl, Timo</creator><creator>Sulk, Mathias</creator><creator>Müller, Frank-Ulrich</creator><creator>Metze, Dieter</creator><creator>Bunnett, Nigel W</creator><creator>Bhargava, Aditi</creator><creator>Carstens, Earl</creator><creator>Furue, Masutaka</creator><creator>Steinhoff, Martin</creator><general>American Society for Clinical Investigation</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>IOV</scope><scope>ISR</scope><scope>3V.</scope><scope>7RV</scope><scope>7X7</scope><scope>7XB</scope><scope>88A</scope><scope>88E</scope><scope>8AO</scope><scope>8FE</scope><scope>8FH</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>ABUWG</scope><scope>AFKRA</scope><scope>AZQEC</scope><scope>BBNVY</scope><scope>BEC</scope><scope>BENPR</scope><scope>BHPHI</scope><scope>CCPQU</scope><scope>DWQXO</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>GNUQQ</scope><scope>HCIFZ</scope><scope>K9.</scope><scope>KB0</scope><scope>LK8</scope><scope>M0S</scope><scope>M1P</scope><scope>M7P</scope><scope>NAPCQ</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PRINS</scope><scope>S0X</scope><scope>7X8</scope><scope>7T5</scope><scope>7TK</scope><scope>H94</scope><scope>5PM</scope></search><sort><creationdate>201406</creationdate><title>Neural peptidase endothelin-converting enzyme 1 regulates endothelin 1-induced pruritus</title><author>Kido-Nakahara, Makiko ; Buddenkotte, Jörg ; Kempkes, Cordula ; Ikoma, Akihiko ; Cevikbas, Ferda ; Akiyama, Tasuku ; Nunes, Frank ; Seeliger, Stephan ; Hasdemir, Burcu ; Mess, Christian ; Buhl, Timo ; Sulk, Mathias ; Müller, Frank-Ulrich ; Metze, Dieter ; Bunnett, Nigel W ; Bhargava, Aditi ; Carstens, Earl ; Furue, Masutaka ; Steinhoff, Martin</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c5913-50917df6b5220ba4395bba6c201f5c683612464f3e52a9a4dcc9b3f3f6f99d0a3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2014</creationdate><topic>Adult</topic><topic>Age</topic><topic>Animals</topic><topic>Aspartic Acid Endopeptidases - antagonists & inhibitors</topic><topic>Aspartic Acid Endopeptidases - genetics</topic><topic>Aspartic Acid Endopeptidases - metabolism</topic><topic>Autoimmune diseases</topic><topic>Biomedical research</topic><topic>Cellular signal transduction</topic><topic>Endothelin-1 - administration & dosage</topic><topic>Endothelin-1 - genetics</topic><topic>Endothelin-1 - metabolism</topic><topic>Endothelin-Converting Enzymes</topic><topic>Enzymes</topic><topic>Female</topic><topic>Ganglia, Spinal - metabolism</topic><topic>Health aspects</topic><topic>Humans</topic><topic>Kinases</topic><topic>Laboratory animals</topic><topic>Male</topic><topic>MAP Kinase Signaling System</topic><topic>Metalloendopeptidases - antagonists & inhibitors</topic><topic>Metalloendopeptidases - genetics</topic><topic>Metalloendopeptidases - metabolism</topic><topic>Mice</topic><topic>Mice, Inbred C57BL</topic><topic>Mice, Knockout</topic><topic>Nervous system</topic><topic>Neurons</topic><topic>Neuropeptides</topic><topic>Pain</topic><topic>Physiological aspects</topic><topic>Proteases</topic><topic>Pruritus</topic><topic>Pruritus - etiology</topic><topic>Pruritus - genetics</topic><topic>Pruritus - metabolism</topic><topic>Receptor, Endothelin A - metabolism</topic><topic>Recycling</topic><topic>Signal Transduction</topic><topic>Skin - innervation</topic><topic>Skin - metabolism</topic><topic>Skin - pathology</topic><topic>Software</topic><topic>Up-Regulation</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Kido-Nakahara, Makiko</creatorcontrib><creatorcontrib>Buddenkotte, Jörg</creatorcontrib><creatorcontrib>Kempkes, Cordula</creatorcontrib><creatorcontrib>Ikoma, Akihiko</creatorcontrib><creatorcontrib>Cevikbas, Ferda</creatorcontrib><creatorcontrib>Akiyama, Tasuku</creatorcontrib><creatorcontrib>Nunes, Frank</creatorcontrib><creatorcontrib>Seeliger, Stephan</creatorcontrib><creatorcontrib>Hasdemir, Burcu</creatorcontrib><creatorcontrib>Mess, Christian</creatorcontrib><creatorcontrib>Buhl, Timo</creatorcontrib><creatorcontrib>Sulk, Mathias</creatorcontrib><creatorcontrib>Müller, Frank-Ulrich</creatorcontrib><creatorcontrib>Metze, Dieter</creatorcontrib><creatorcontrib>Bunnett, Nigel W</creatorcontrib><creatorcontrib>Bhargava, Aditi</creatorcontrib><creatorcontrib>Carstens, Earl</creatorcontrib><creatorcontrib>Furue, Masutaka</creatorcontrib><creatorcontrib>Steinhoff, Martin</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Opposing Viewpoints in Context (Gale)</collection><collection>Gale In Context: Science</collection><collection>ProQuest Central (Corporate)</collection><collection>ProQuest Nursing and Allied Health Journals</collection><collection>Health & Medical Collection</collection><collection>ProQuest Central (purchase pre-March 2016)</collection><collection>Biology Database (Alumni Edition)</collection><collection>Medical Database (Alumni Edition)</collection><collection>ProQuest Pharma Collection</collection><collection>ProQuest SciTech Collection</collection><collection>ProQuest Natural Science Collection</collection><collection>Hospital Premium Collection</collection><collection>Hospital Premium Collection (Alumni Edition)</collection><collection>ProQuest Central (Alumni) (purchase pre-March 2016)</collection><collection>ProQuest Central (Alumni)</collection><collection>ProQuest Central</collection><collection>ProQuest Central Essentials</collection><collection>Biological Science Collection</collection><collection>eLibrary</collection><collection>ProQuest Central</collection><collection>ProQuest Natural Science Collection</collection><collection>ProQuest One Community College</collection><collection>ProQuest Central Korea</collection><collection>Health Research Premium Collection</collection><collection>Health Research Premium Collection (Alumni)</collection><collection>ProQuest Central Student</collection><collection>SciTech Premium Collection</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>Nursing & Allied Health Database (Alumni Edition)</collection><collection>ProQuest Biological Science Collection</collection><collection>Health & Medical Collection (Alumni Edition)</collection><collection>Medical Database</collection><collection>Biological Science Database</collection><collection>Nursing & Allied Health Premium</collection><collection>ProQuest One Academic Eastern Edition (DO NOT USE)</collection><collection>ProQuest One Academic</collection><collection>ProQuest One Academic UKI Edition</collection><collection>ProQuest Central China</collection><collection>SIRS Editorial</collection><collection>MEDLINE - Academic</collection><collection>Immunology Abstracts</collection><collection>Neurosciences Abstracts</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>The Journal of clinical investigation</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Kido-Nakahara, Makiko</au><au>Buddenkotte, Jörg</au><au>Kempkes, Cordula</au><au>Ikoma, Akihiko</au><au>Cevikbas, Ferda</au><au>Akiyama, Tasuku</au><au>Nunes, Frank</au><au>Seeliger, Stephan</au><au>Hasdemir, Burcu</au><au>Mess, Christian</au><au>Buhl, Timo</au><au>Sulk, Mathias</au><au>Müller, Frank-Ulrich</au><au>Metze, Dieter</au><au>Bunnett, Nigel W</au><au>Bhargava, Aditi</au><au>Carstens, Earl</au><au>Furue, Masutaka</au><au>Steinhoff, Martin</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Neural peptidase endothelin-converting enzyme 1 regulates endothelin 1-induced pruritus</atitle><jtitle>The Journal of clinical investigation</jtitle><addtitle>J Clin Invest</addtitle><date>2014-06</date><risdate>2014</risdate><volume>124</volume><issue>6</issue><spage>2683</spage><epage>2695</epage><pages>2683-2695</pages><issn>0021-9738</issn><eissn>1558-8238</eissn><notes>ObjectType-Article-1</notes><notes>SourceType-Scholarly Journals-1</notes><notes>ObjectType-Feature-2</notes><notes>content type line 23</notes><notes>Authorship note: Makiko Kido-Nakahara, Jörg Buddenkotte, and Cordula Kempkes contributed equally to this work.</notes><abstract>In humans, pruritus (itch) is a common but poorly understood symptom in numerous skin and systemic diseases. Endothelin 1 (ET-1) evokes histamine-independent pruritus in mammals through activation of its cognate G protein-coupled receptor endothelin A receptor (ETAR). Here, we have identified neural endothelin-converting enzyme 1 (ECE-1) as a key regulator of ET-1-induced pruritus and neural signaling of itch. We show here that ETAR, ET-1, and ECE-1 are expressed and colocalize in murine dorsal root ganglia (DRG) neurons and human skin nerves. In murine DRG neurons, ET-1 induced internalization of ETAR within ECE-1-containing endosomes. ECE-1 inhibition slowed ETAR recycling yet prolonged ET-1-induced activation of ERK1/2, but not p38. In a murine itch model, ET-1-induced scratching behavior was substantially augmented by pharmacological ECE-1 inhibition and abrogated by treatment with an ERK1/2 inhibitor. Using iontophoresis, we demonstrated that ET-1 is a potent, partially histamine-independent pruritogen in humans. Immunohistochemical evaluation of skin from prurigo nodularis patients confirmed an upregulation of the ET-1/ETAR/ECE-1/ERK1/2 axis in patients with chronic itch. Together, our data identify the neural peptidase ECE-1 as a negative regulator of itch on sensory nerves by directly regulating ET-1-induced pruritus in humans and mice. Furthermore, these results implicate the ET-1/ECE-1/ERK1/2 pathway as a therapeutic target to treat pruritus in humans.</abstract><cop>United States</cop><pub>American Society for Clinical Investigation</pub><pmid>24812665</pmid><doi>10.1172/JCI67323</doi><tpages>13</tpages><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 0021-9738 |
| ispartof | The Journal of clinical investigation, 2014-06, Vol.124 (6), p.2683-2695 |
| issn | 0021-9738 1558-8238 |
| language | eng |
| recordid | cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_4038561 |
| source | PubMed Central; EZB Electronic Journals Library |
| subjects | Adult Age Animals Aspartic Acid Endopeptidases - antagonists & inhibitors Aspartic Acid Endopeptidases - genetics Aspartic Acid Endopeptidases - metabolism Autoimmune diseases Biomedical research Cellular signal transduction Endothelin-1 - administration & dosage Endothelin-1 - genetics Endothelin-1 - metabolism Endothelin-Converting Enzymes Enzymes Female Ganglia, Spinal - metabolism Health aspects Humans Kinases Laboratory animals Male MAP Kinase Signaling System Metalloendopeptidases - antagonists & inhibitors Metalloendopeptidases - genetics Metalloendopeptidases - metabolism Mice Mice, Inbred C57BL Mice, Knockout Nervous system Neurons Neuropeptides Pain Physiological aspects Proteases Pruritus Pruritus - etiology Pruritus - genetics Pruritus - metabolism Receptor, Endothelin A - metabolism Recycling Signal Transduction Skin - innervation Skin - metabolism Skin - pathology Software Up-Regulation |
| title | Neural peptidase endothelin-converting enzyme 1 regulates endothelin 1-induced pruritus |
| url | http://sfxeu10.hosted.exlibrisgroup.com/loughborough?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2024-09-21T17%3A40%3A49IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-gale_pubme&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=Neural%20peptidase%20endothelin-converting%20enzyme%201%20regulates%20endothelin%201-induced%20pruritus&rft.jtitle=The%20Journal%20of%20clinical%20investigation&rft.au=Kido-Nakahara,%20Makiko&rft.date=2014-06&rft.volume=124&rft.issue=6&rft.spage=2683&rft.epage=2695&rft.pages=2683-2695&rft.issn=0021-9738&rft.eissn=1558-8238&rft_id=info:doi/10.1172/JCI67323&rft_dat=%3Cgale_pubme%3EA372250832%3C/gale_pubme%3E%3Cgrp_id%3Ecdi_FETCH-LOGICAL-c5913-50917df6b5220ba4395bba6c201f5c683612464f3e52a9a4dcc9b3f3f6f99d0a3%3C/grp_id%3E%3Coa%3E%3C/oa%3E%3Curl%3E%3C/url%3E&rft_id=info:oai/&rft_pqid=1539277666&rft_id=info:pmid/24812665&rft_galeid=A372250832&rfr_iscdi=true |