Mechanism of external K+ sensitivity of KCNQ1 channels
KCNQ1 voltage-gated K+ channels are involved in a wide variety of fundamental physiological processes and exhibit the unique feature of being markedly inhibited by external K+. Despite the potential role of this regulatory mechanism in distinct physiological and pathological processes, its exact und...
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| Veröffentlicht in: | The Journal of general physiology 2023-05, Vol.155 (5), p.1 |
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| creator | Abrahamyan, Astghik Eldstrom, Jodene Sahakyan, Harutyun Karagulyan, Nare Mkrtchyan, Liana Karapetyan, Tatev Sargsyan, Ernest Kneussel, Matthias Nazaryan, Karen Schwarz, Jürgen R Fedida, David Vardanyan, Vitya |
| description | KCNQ1 voltage-gated K+ channels are involved in a wide variety of fundamental physiological processes and exhibit the unique feature of being markedly inhibited by external K+. Despite the potential role of this regulatory mechanism in distinct physiological and pathological processes, its exact underpinnings are not well understood. In this study, using extensive mutagenesis, molecular dynamics simulations, and single-channel recordings, we delineate the molecular mechanism of KCNQ1 modulation by external K+. First, we demonstrate the involvement of the selectivity filter in the external K+ sensitivity of the channel. Then, we show that external K+ binds to the vacant outermost ion coordination site of the selectivity filter inducing a diminution in the unitary conductance of the channel. The larger reduction in the unitary conductance compared to whole-cell currents suggests an additional modulatory effect of external K+ on the channel. Further, we show that the external K+ sensitivity of the heteromeric KCNQ1/KCNE complexes depends on the type of associated KCNE subunits. |
| doi_str_mv | 10.1085/jgp.202213205 |
| format | Article |
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Despite the potential role of this regulatory mechanism in distinct physiological and pathological processes, its exact underpinnings are not well understood. In this study, using extensive mutagenesis, molecular dynamics simulations, and single-channel recordings, we delineate the molecular mechanism of KCNQ1 modulation by external K+. First, we demonstrate the involvement of the selectivity filter in the external K+ sensitivity of the channel. Then, we show that external K+ binds to the vacant outermost ion coordination site of the selectivity filter inducing a diminution in the unitary conductance of the channel. The larger reduction in the unitary conductance compared to whole-cell currents suggests an additional modulatory effect of external K+ on the channel. Further, we show that the external K+ sensitivity of the heteromeric KCNQ1/KCNE complexes depends on the type of associated KCNE subunits.</description><identifier>ISSN: 0022-1295</identifier><identifier>EISSN: 1540-7748</identifier><identifier>DOI: 10.1085/jgp.202213205</identifier><identifier>PMID: 36809486</identifier><language>eng</language><publisher>United States: Rockefeller University Press</publisher><subject>Biophysics ; Cellular Physiology ; Channel gating ; Ions ; KCNQ1 Potassium Channel - metabolism ; KCNQ1 protein ; Membrane Transport ; Molecular dynamics ; Molecular Dynamics Simulation ; Molecular modelling ; Mutagenesis ; Oocytes - metabolism ; Patch-Clamp Techniques ; Physiology ; Potassium ; Potassium channels (voltage-gated) ; Potassium Channels, Voltage-Gated - metabolism ; Protein Structure and Dynamics</subject><ispartof>The Journal of general physiology, 2023-05, Vol.155 (5), p.1</ispartof><rights>2023 Abrahamyan et al.</rights><rights>Copyright Rockefeller University Press May 2023</rights><rights>2023 Abrahamyan et al. 2023</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c415t-627f2a198939e1827a9862079f0cedec413c14da903a282c6f4675a2ce8ff5df3</citedby><cites>FETCH-LOGICAL-c415t-627f2a198939e1827a9862079f0cedec413c14da903a282c6f4675a2ce8ff5df3</cites><orcidid>0000-0001-8561-050X ; 0000-0001-6797-5185 ; 0000-0002-7684-175X ; 0000-0003-4900-366X ; 0000-0001-6731-036X ; 0000-0003-3750-8118 ; 0000-0002-5231-3928</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>230,314,776,780,881,27901,27902</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/36809486$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Abrahamyan, Astghik</creatorcontrib><creatorcontrib>Eldstrom, Jodene</creatorcontrib><creatorcontrib>Sahakyan, Harutyun</creatorcontrib><creatorcontrib>Karagulyan, Nare</creatorcontrib><creatorcontrib>Mkrtchyan, Liana</creatorcontrib><creatorcontrib>Karapetyan, Tatev</creatorcontrib><creatorcontrib>Sargsyan, Ernest</creatorcontrib><creatorcontrib>Kneussel, Matthias</creatorcontrib><creatorcontrib>Nazaryan, Karen</creatorcontrib><creatorcontrib>Schwarz, Jürgen R</creatorcontrib><creatorcontrib>Fedida, David</creatorcontrib><creatorcontrib>Vardanyan, Vitya</creatorcontrib><title>Mechanism of external K+ sensitivity of KCNQ1 channels</title><title>The Journal of general physiology</title><addtitle>J Gen Physiol</addtitle><description>KCNQ1 voltage-gated K+ channels are involved in a wide variety of fundamental physiological processes and exhibit the unique feature of being markedly inhibited by external K+. Despite the potential role of this regulatory mechanism in distinct physiological and pathological processes, its exact underpinnings are not well understood. In this study, using extensive mutagenesis, molecular dynamics simulations, and single-channel recordings, we delineate the molecular mechanism of KCNQ1 modulation by external K+. First, we demonstrate the involvement of the selectivity filter in the external K+ sensitivity of the channel. Then, we show that external K+ binds to the vacant outermost ion coordination site of the selectivity filter inducing a diminution in the unitary conductance of the channel. The larger reduction in the unitary conductance compared to whole-cell currents suggests an additional modulatory effect of external K+ on the channel. Further, we show that the external K+ sensitivity of the heteromeric KCNQ1/KCNE complexes depends on the type of associated KCNE subunits.</description><subject>Biophysics</subject><subject>Cellular Physiology</subject><subject>Channel gating</subject><subject>Ions</subject><subject>KCNQ1 Potassium Channel - metabolism</subject><subject>KCNQ1 protein</subject><subject>Membrane Transport</subject><subject>Molecular dynamics</subject><subject>Molecular Dynamics Simulation</subject><subject>Molecular modelling</subject><subject>Mutagenesis</subject><subject>Oocytes - metabolism</subject><subject>Patch-Clamp Techniques</subject><subject>Physiology</subject><subject>Potassium</subject><subject>Potassium channels (voltage-gated)</subject><subject>Potassium Channels, Voltage-Gated - metabolism</subject><subject>Protein Structure and Dynamics</subject><issn>0022-1295</issn><issn>1540-7748</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2023</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNpdkc1Lw0AQxRdRbK0evUrAiyCps5vs10WQ4hetiqDnZd3stlvSpGaTYv97E1qLOpeBeT8eM_MQOsUwxCDo1Xy6HBIgBCcE6B7qY5pCzHkq9lEf2nmMiaQ9dBTCHNqiBA5RL2ECZCpYH7Ena2a68GERlS6yX7WtCp1H48so2CL42q98ve6k8ej5FUcdW9g8HKMDp_NgT7Z9gN7vbt9GD_Hk5f5xdDOJTYppHTPCHdFYCplIiwXhWgpGgEsHxma2hRKD00xLSDQRxDCXMk41MVY4RzOXDND1xnfZfCxsZmxRVzpXy8ovdLVWpfbqr1L4mZqWKyUlA-C4NbjYGlTlZ2NDrRY-GJvnurBlExThXEgBFNIWPf-Hzsum-0ZLCRCMcQydYbyhTFWGUFm3WwaD6hJRbSJql0jLn_2-YEf_RJB8A900hUs</recordid><startdate>20230501</startdate><enddate>20230501</enddate><creator>Abrahamyan, Astghik</creator><creator>Eldstrom, Jodene</creator><creator>Sahakyan, Harutyun</creator><creator>Karagulyan, Nare</creator><creator>Mkrtchyan, Liana</creator><creator>Karapetyan, Tatev</creator><creator>Sargsyan, Ernest</creator><creator>Kneussel, Matthias</creator><creator>Nazaryan, Karen</creator><creator>Schwarz, Jürgen R</creator><creator>Fedida, David</creator><creator>Vardanyan, Vitya</creator><general>Rockefeller University Press</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>7QR</scope><scope>7TK</scope><scope>7TS</scope><scope>8FD</scope><scope>FR3</scope><scope>K9.</scope><scope>P64</scope><scope>7X8</scope><scope>5PM</scope><orcidid>https://orcid.org/0000-0001-8561-050X</orcidid><orcidid>https://orcid.org/0000-0001-6797-5185</orcidid><orcidid>https://orcid.org/0000-0002-7684-175X</orcidid><orcidid>https://orcid.org/0000-0003-4900-366X</orcidid><orcidid>https://orcid.org/0000-0001-6731-036X</orcidid><orcidid>https://orcid.org/0000-0003-3750-8118</orcidid><orcidid>https://orcid.org/0000-0002-5231-3928</orcidid></search><sort><creationdate>20230501</creationdate><title>Mechanism of external K+ sensitivity of KCNQ1 channels</title><author>Abrahamyan, Astghik ; Eldstrom, Jodene ; Sahakyan, Harutyun ; Karagulyan, Nare ; Mkrtchyan, Liana ; Karapetyan, Tatev ; Sargsyan, Ernest ; Kneussel, Matthias ; Nazaryan, Karen ; Schwarz, Jürgen R ; Fedida, David ; Vardanyan, Vitya</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c415t-627f2a198939e1827a9862079f0cedec413c14da903a282c6f4675a2ce8ff5df3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2023</creationdate><topic>Biophysics</topic><topic>Cellular Physiology</topic><topic>Channel gating</topic><topic>Ions</topic><topic>KCNQ1 Potassium Channel - metabolism</topic><topic>KCNQ1 protein</topic><topic>Membrane Transport</topic><topic>Molecular dynamics</topic><topic>Molecular Dynamics Simulation</topic><topic>Molecular modelling</topic><topic>Mutagenesis</topic><topic>Oocytes - metabolism</topic><topic>Patch-Clamp Techniques</topic><topic>Physiology</topic><topic>Potassium</topic><topic>Potassium channels (voltage-gated)</topic><topic>Potassium Channels, Voltage-Gated - metabolism</topic><topic>Protein Structure and Dynamics</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Abrahamyan, Astghik</creatorcontrib><creatorcontrib>Eldstrom, Jodene</creatorcontrib><creatorcontrib>Sahakyan, Harutyun</creatorcontrib><creatorcontrib>Karagulyan, Nare</creatorcontrib><creatorcontrib>Mkrtchyan, Liana</creatorcontrib><creatorcontrib>Karapetyan, Tatev</creatorcontrib><creatorcontrib>Sargsyan, Ernest</creatorcontrib><creatorcontrib>Kneussel, Matthias</creatorcontrib><creatorcontrib>Nazaryan, Karen</creatorcontrib><creatorcontrib>Schwarz, Jürgen R</creatorcontrib><creatorcontrib>Fedida, David</creatorcontrib><creatorcontrib>Vardanyan, Vitya</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>Chemoreception Abstracts</collection><collection>Neurosciences Abstracts</collection><collection>Physical Education Index</collection><collection>Technology Research Database</collection><collection>Engineering Research Database</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>The Journal of general physiology</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Abrahamyan, Astghik</au><au>Eldstrom, Jodene</au><au>Sahakyan, Harutyun</au><au>Karagulyan, Nare</au><au>Mkrtchyan, Liana</au><au>Karapetyan, Tatev</au><au>Sargsyan, Ernest</au><au>Kneussel, Matthias</au><au>Nazaryan, Karen</au><au>Schwarz, Jürgen R</au><au>Fedida, David</au><au>Vardanyan, Vitya</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Mechanism of external K+ sensitivity of KCNQ1 channels</atitle><jtitle>The Journal of general physiology</jtitle><addtitle>J Gen Physiol</addtitle><date>2023-05-01</date><risdate>2023</risdate><volume>155</volume><issue>5</issue><spage>1</spage><pages>1-</pages><issn>0022-1295</issn><eissn>1540-7748</eissn><abstract>KCNQ1 voltage-gated K+ channels are involved in a wide variety of fundamental physiological processes and exhibit the unique feature of being markedly inhibited by external K+. 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| subjects | Biophysics Cellular Physiology Channel gating Ions KCNQ1 Potassium Channel - metabolism KCNQ1 protein Membrane Transport Molecular dynamics Molecular Dynamics Simulation Molecular modelling Mutagenesis Oocytes - metabolism Patch-Clamp Techniques Physiology Potassium Potassium channels (voltage-gated) Potassium Channels, Voltage-Gated - metabolism Protein Structure and Dynamics |
| title | Mechanism of external K+ sensitivity of KCNQ1 channels |
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