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  1. Article ; Online: A channelopathy mechanism revealed by direct calmodulin activation of TrpV4.

    Loukin, Stephen H / Teng, Jinfeng / Kung, Ching

    Proceedings of the National Academy of Sciences of the United States of America

    2015  Volume 112, Issue 30, Page(s) 9400–9405

    Abstract: Ca(2+)-calmodulin (CaM) regulates varieties of ion channels, including Transient Receptor Potential vanilloid subtype 4 (TrpV4). It has previously been proposed that internal Ca(2+) increases TrpV4 activity through Ca(2+)-CaM binding to a C-terminal Ca(2+ ...

    Abstract Ca(2+)-calmodulin (CaM) regulates varieties of ion channels, including Transient Receptor Potential vanilloid subtype 4 (TrpV4). It has previously been proposed that internal Ca(2+) increases TrpV4 activity through Ca(2+)-CaM binding to a C-terminal Ca(2+)-CaM binding domain (CBD). We confirmed this model by directly presenting Ca(2+)-CaM protein to membrane patches excised from TrpV4-expressing oocytes. Over 50 TRPV4 mutations are now known to cause heritable skeletal dysplasia (SD) and other diseases in human. We have previously examined 14 SD alleles and found them to all have gain-of-function effects, with the gain of constitutive open probability paralleling disease severity. Among the 14 SD alleles examined, E797K and P799L are located immediate upstream of the CBD. They not only have increase basal activity, but, unlike the wild-type or other SD-mutant channels examined, they were greatly reduced in their response to Ca(2+)-CaM. Deleting a 10-residue upstream peptide (Δ795-804) that covers the two SD mutant sites resulted in strong constitutive activity and the complete lack of Ca(2+)-CaM response. We propose that the region immediately upstream of CBD is an autoinhibitory domain that maintains the closed state through electrostatic interactions, and adjacent detachable Ca(2+)-CaM binding to CBD sterically interferes with this autoinhibition. This work further supports the notion that TrpV4 mutations cause SD by constitutive leakage. However, the closed conformation is likely destabilized by various mutations by different mechanisms, including the permanent removal of an autoinhibition documented here.
    MeSH term(s) Alleles ; Amino Acid Sequence ; Animals ; Binding Sites ; Bone Diseases/genetics ; Bone Diseases/physiopathology ; Calcium/chemistry ; Calmodulin/chemistry ; Channelopathies/physiopathology ; Chelating Agents/chemistry ; Gene Expression Profiling ; Humans ; Ion Channel Gating ; Molecular Sequence Data ; Mutation ; Oocytes/cytology ; Protein Binding/genetics ; Protein Structure, Tertiary ; RNA, Complementary/metabolism ; Sequence Homology, Amino Acid ; TRPV Cation Channels/genetics ; TRPV Cation Channels/physiology ; Xenopus laevis
    Chemical Substances Calmodulin ; Chelating Agents ; RNA, Complementary ; TRPV Cation Channels ; TRPV4 protein, human ; Calcium (SY7Q814VUP)
    Language English
    Publishing date 2015-07-13
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 209104-5
    ISSN 1091-6490 ; 0027-8424
    ISSN (online) 1091-6490
    ISSN 0027-8424
    DOI 10.1073/pnas.1510602112
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  2. Article: A channelopathy mechanism revealed by direct calmodulin activation of TrpV4

    Loukin, Stephen H / Jinfeng Teng / Ching Kung

    Proceedings of the National Academy of Sciences of the United States of America. 2015 July 28, v. 112, no. 30

    2015  

    Abstract: Over 50 mutations in the ion channel Transient Receptor Potential vanilloid subtype 4 (TrpV4) cause diseases ranging from dwarfism to prenatal death. We previously examined 14 mutant channels and found them to leak. Ca ²⁺ encourages TrpV4 opening ... ...

    Abstract Over 50 mutations in the ion channel Transient Receptor Potential vanilloid subtype 4 (TrpV4) cause diseases ranging from dwarfism to prenatal death. We previously examined 14 mutant channels and found them to leak. Ca ²⁺ encourages TrpV4 opening through calmodulin (CaM). Here, we examined two channels mutated in close proximity to the Ca ²⁺-CaM–binding domain. They not only leak but also are greatly reduced in activation by Ca ²⁺-CaM compared with the wild-type or other mutant channels. These mutations likely define an autoinhibitory domain that keeps the channel closed, to which adjacent detachable Ca ²⁺-CaM binding interferes with this inhibition. The scattered disease alleles may all make the channel leak but apparently by different means, including the loss of an autoinhibition shown here.

    Ca ²⁺-calmodulin (CaM) regulates varieties of ion channels, including Transient Receptor Potential vanilloid subtype 4 (TrpV4). It has previously been proposed that internal Ca ²⁺ increases TrpV4 activity through Ca ²⁺-CaM binding to a C-terminal Ca ²⁺-CaM binding domain (CBD). We confirmed this model by directly presenting Ca ²⁺-CaM protein to membrane patches excised from TrpV4-expressing oocytes. Over 50 TRPV4 mutations are now known to cause heritable skeletal dysplasia (SD) and other diseases in human. We have previously examined 14 SD alleles and found them to all have gain-of-function effects, with the gain of constitutive open probability paralleling disease severity. Among the 14 SD alleles examined, E797K and P799L are located immediate upstream of the CBD. They not only have increase basal activity, but, unlike the wild-type or other SD-mutant channels examined, they were greatly reduced in their response to Ca ²⁺-CaM. Deleting a 10-residue upstream peptide (Δ795–804) that covers the two SD mutant sites resulted in strong constitutive activity and the complete lack of Ca ²⁺-CaM response. We propose that the region immediately upstream of CBD is an autoinhibitory domain that maintains the closed state through electrostatic interactions, and adjacent detachable Ca ²⁺-CaM binding to CBD sterically interferes with this autoinhibition. This work further supports the notion that TrpV4 mutations cause SD by constitutive leakage. However, the closed conformation is likely destabilized by various mutations by different mechanisms, including the permanent removal of an autoinhibition documented here.
    Keywords alleles ; calcium ; calmodulin ; death ; mutants ; mutation ; transient receptor potential channels ; skeletal dysplasia ; ion channel ; autoinhibition ; TrpV1
    Language English
    Dates of publication 2015-0728
    Size p. 9400-9405.
    Publishing place National Academy of Sciences
    Document type Article
    ZDB-ID 209104-5
    ISSN 1091-6490 ; 0027-8424
    ISSN (online) 1091-6490
    ISSN 0027-8424
    DOI 10.1073/pnas.1510602112
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  3. Article ; Online: A competing hydrophobic tug on L596 to the membrane core unlatches S4-S5 linker elbow from TRP helix and allows TRPV4 channel to open.

    Teng, Jinfeng / Loukin, Stephen H / Anishkin, Andriy / Kung, Ching

    Proceedings of the National Academy of Sciences of the United States of America

    2016  Volume 113, Issue 42, Page(s) 11847–11852

    Abstract: ... simulations showed that the distance between the levels of α-carbons of H-bonded residues L596 and W733 is ...

    Abstract We have some generalized physical understanding of how ion channels interact with surrounding lipids but few detailed descriptions on how interactions of particular amino acids with contacting lipids may regulate gating. Here we discovered a structure-specific interaction between an amino acid and inner-leaflet lipid that governs the gating transformations of TRPV4 (transient receptor potential vanilloid type 4). Many cation channels use a S4-S5 linker to transmit stimuli to the gate. At the start of TRPV4's linker helix is leucine 596. A hydrogen bond between the indole of W733 of the TRP helix and the backbone oxygen of L596 secures the helix/linker contact, which acts as a latch maintaining channel closure. The modeled side chain of L596 interacts with the inner lipid leaflet near the polar-nonpolar interface in our model-an interaction that we explored by mutagenesis. We examined the outward currents of TRPV4-expressing Xenopus oocyte upon depolarizations as well as phenotypes of expressing yeast cells. Making this residue less hydrophobic (L596A/G/W/Q/K) reduces open probability [Po; loss-of-function (LOF)], likely due to altered interactions at the polar-nonpolar interface. L596I raises Po [gain-of-function (GOF)], apparently by placing its methyl group further inward and receiving stronger water repulsion. Molecular dynamics simulations showed that the distance between the levels of α-carbons of H-bonded residues L596 and W733 is shortened in the LOFs and lengthened in the GOFs, strengthening or weakening the linker/TRP helix latch, respectively. These results highlight that L596 lipid attraction counteracts the latch bond in a tug-of-war to tune the Po of TRPV4.
    MeSH term(s) Amino Acid Sequence ; Amino Acids/chemistry ; Animals ; Gain of Function Mutation ; Hydrogen Bonding ; Hydrophobic and Hydrophilic Interactions ; Ion Channel Gating/drug effects ; Lipids/chemistry ; Loss of Function Mutation ; Membranes/chemistry ; Membranes/metabolism ; Models, Molecular ; Phenotype ; Protein Conformation ; Protein Interaction Domains and Motifs ; Structure-Activity Relationship ; TRPV Cation Channels/agonists ; TRPV Cation Channels/chemistry ; TRPV Cation Channels/genetics ; TRPV Cation Channels/metabolism ; Xenopus ; Yeasts/genetics ; Yeasts/metabolism
    Chemical Substances Amino Acids ; Lipids ; TRPV Cation Channels
    Language English
    Publishing date 2016-10-03
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 209104-5
    ISSN 1091-6490 ; 0027-8424
    ISSN (online) 1091-6490
    ISSN 0027-8424
    DOI 10.1073/pnas.1613523113
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  4. Article ; Online: L596-W733 bond between the start of the S4-S5 linker and the TRP box stabilizes the closed state of TRPV4 channel.

    Teng, Jinfeng / Loukin, Stephen H / Anishkin, Andriy / Kung, Ching

    Proceedings of the National Academy of Sciences of the United States of America

    2015  Volume 112, Issue 11, Page(s) 3386–3391

    Abstract: Unlike other cation channels, each subunit of most transient receptor potential (TRP) channels has an additional TRP-domain helix with an invariant tryptophan immediately trailing the gate-bearing S6. Recent cryo-electron microscopy of TRP vanilloid ... ...

    Abstract Unlike other cation channels, each subunit of most transient receptor potential (TRP) channels has an additional TRP-domain helix with an invariant tryptophan immediately trailing the gate-bearing S6. Recent cryo-electron microscopy of TRP vanilloid subfamily, member 1 structures revealed that this domain is a five-turn amphipathic helix, and the invariant tryptophan forms a bond with the beginning of the four-turn S4-S5 linker helix. By homology modeling, we identified the corresponding L596-W733 bond in TRP vanilloid subfamily, member 4 (TRPV4). The L596P mutation blocks bone development in Kozlowski-type spondylometaphyseal dysplasia in human. Our previous screen also isolated W733R as a strong gain-of-function (GOF) mutation that suppresses growth when the W733R channel is expressed in yeast. We show that, when expressed in Xenopus oocytes, TRPV4 with the L596P or W733R mutation displays normal depolarization-induced activation and outward rectification. However, these mutant channels have higher basal open probabilities and limited responses to the agonist GSK1016790A, explaining their biological GOF phenotypes. In addition, W733R current fails to inactivate during depolarization. Systematic replacement of W733 with amino acids of different properties produced similar electrophysiological and yeast phenotypes. The results can be interpreted consistently in the context of the homology model of TRPV4 molecule we have developed and refined using simulations in explicit medium. We propose that this bond maintains the orientation of the S4-S5 linker to keep the S6 gate closed. Further, the two partner helices, both amphipathic and located at the polar-nonpolar interface of the inner lipid monolayer, may receive and integrate various physiological stimuli.
    MeSH term(s) Amino Acid Substitution ; Animals ; Humans ; Ion Channel Gating ; Leucine/chemistry ; Mutant Proteins/chemistry ; Mutant Proteins/metabolism ; Mutation/genetics ; Oocytes ; Phenotype ; Protein Stability ; Protein Structure, Secondary ; Saccharomyces cerevisiae/growth & development ; Structure-Activity Relationship ; TRPV Cation Channels/chemistry ; TRPV Cation Channels/genetics ; TRPV Cation Channels/metabolism ; Tryptophan/chemistry ; Xenopus
    Chemical Substances Mutant Proteins ; TRPV Cation Channels ; TRPV4 protein, human ; Tryptophan (8DUH1N11BX) ; Leucine (GMW67QNF9C)
    Language English
    Publishing date 2015-03-17
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 209104-5
    ISSN 1091-6490 ; 0027-8424
    ISSN (online) 1091-6490
    ISSN 0027-8424
    DOI 10.1073/pnas.1502366112
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  5. Article ; Online: Feeling the hidden mechanical forces in lipid bilayer is an original sense.

    Anishkin, Andriy / Loukin, Stephen H / Teng, Jinfeng / Kung, Ching

    Proceedings of the National Academy of Sciences of the United States of America

    2014  Volume 111, Issue 22, Page(s) 7898–7905

    Abstract: Life's origin entails enclosing a compartment to hoard material, energy, and information. The envelope necessarily comprises amphipaths, such as prebiotic fatty acids, to partition the two aqueous domains. The self-assembled lipid bilayer comes with a ... ...

    Abstract Life's origin entails enclosing a compartment to hoard material, energy, and information. The envelope necessarily comprises amphipaths, such as prebiotic fatty acids, to partition the two aqueous domains. The self-assembled lipid bilayer comes with a set of properties including its strong anisotropic internal forces that are chemically or physically malleable. Added bilayer stretch can alter force vectors on embedded proteins to effect conformational change. The force-from-lipid principle was demonstrated 25 y ago when stretches opened purified Escherichia coli MscL channels reconstituted into artificial bilayers. This reductionistic exercise has rigorously been recapitulated recently with two vertebrate mechanosensitive K(+) channels (TREK1 and TRAAK). Membrane stretches have also been known to activate various voltage-, ligand-, or Ca(2+)-gated channels. Careful analyses showed that Kv, the canonical voltage-gated channel, is in fact exquisitely sensitive even to very small tension. In an unexpected context, the canonical transient-receptor-potential channels in the Drosophila eye, long presumed to open by ligand binding, is apparently opened by membrane force due to PIP2 hydrolysis-induced changes in bilayer strain. Being the intimate medium, lipids govern membrane proteins by physics as well as chemistry. This principle should not be a surprise because it parallels water's paramount role in the structure and function of soluble proteins. Today, overt or covert mechanical forces govern cell biological processes and produce sensations. At the genesis, a bilayer's response to osmotic force is likely among the first senses to deal with the capricious primordial sea.
    MeSH term(s) Animals ; Biological Evolution ; Humans ; Ion Channel Gating/physiology ; Lipid Bilayers/chemistry ; Mechanotransduction, Cellular/physiology ; Origin of Life ; Osmotic Pressure ; Stress, Mechanical ; Touch/physiology
    Chemical Substances Lipid Bilayers
    Language English
    Publishing date 2014-05-21
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Review
    ZDB-ID 209104-5
    ISSN 1091-6490 ; 0027-8424
    ISSN (online) 1091-6490
    ISSN 0027-8424
    DOI 10.1073/pnas.1313364111
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  6. Article ; Online: Hypotonic shocks activate rat TRPV4 in yeast in the absence of polyunsaturated fatty acids.

    Loukin, Stephen H / Su, Zhenwei / Kung, Ching

    FEBS letters

    2009  Volume 583, Issue 4, Page(s) 754–758

    Abstract: Transient-receptor-potential channels (TRPs) underlie the sensing of chemicals, heat, and mechanical force. We expressed the rat TRPV1 and TRPV4 subtypes in yeast and monitored their activities in vivo as Ca(2+) rise using transgenic aequorin. Heat and ... ...

    Abstract Transient-receptor-potential channels (TRPs) underlie the sensing of chemicals, heat, and mechanical force. We expressed the rat TRPV1 and TRPV4 subtypes in yeast and monitored their activities in vivo as Ca(2+) rise using transgenic aequorin. Heat and capsaicin activate TRPV1 but not TRPV4 in yeast. Hypotonic shocks activate TRPV4 but not TRPV1. Osmotic swelling is modeled to activate enzyme(s), producing polyunsaturated fatty acids (PUFAs) to open TRPV4 in mammalian cells. This model relegates mechanosensitivity to the enzyme and not the channel. Yeast has only a single Delta9 fatty-acid monodesaturase and cannot make PUFAs suggesting an alternative mechanism for TRPV4 activation. We discuss possible explanations of this difference.
    MeSH term(s) Animals ; Fatty Acids, Unsaturated/genetics ; Hypotonic Solutions/pharmacology ; Ion Channels/classification ; Ion Channels/genetics ; Ion Channels/metabolism ; Rats ; Saccharomyces cerevisiae/genetics ; Saccharomyces cerevisiae/metabolism ; TRPV Cation Channels/genetics ; TRPV Cation Channels/metabolism
    Chemical Substances Fatty Acids, Unsaturated ; Hypotonic Solutions ; Ion Channels ; TRPV Cation Channels ; Trpv4 protein, rat
    Language English
    Publishing date 2009-01-25
    Publishing country England
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 212746-5
    ISSN 1873-3468 ; 0014-5793
    ISSN (online) 1873-3468
    ISSN 0014-5793
    DOI 10.1016/j.febslet.2009.01.027
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  7. Article: Carboxyl tail prevents yeast K(+) channel closure: proposal of an integrated model of TOK1 gating.

    Loukin, Stephen H / Saimi, Yoshiro

    Biophysical journal

    2002  Volume 82, Issue 2, Page(s) 781–792

    Abstract: TOK1 encodes the channel responsible for the prominent outward K(+) current of the yeast plasma membrane. It can dwell in several impermeable states, including a rapidly transiting, K(+)-electromotive-force-dependent "R" (rectifying) state, a voltage- ... ...

    Abstract TOK1 encodes the channel responsible for the prominent outward K(+) current of the yeast plasma membrane. It can dwell in several impermeable states, including a rapidly transiting, K(+)-electromotive-force-dependent "R" (rectifying) state, a voltage-independent "IB" (interburst) state, and a set of [K(+)](ext) and voltage-dependent "C" (closed) states. Whereas evidence suggests that the C states result from the constriction of an inner gate at the cytosolic end of the pore, R is most likely an intrinsic gating property of the K(+) filter. Here, we present evidence that Tok1's carboxyl-tail domain also plays an intimate role in channel gating by dynamically preventing inner-gate closures. We present an integrated model of TOK1 gating in which the filter gate, inner gate, and carboxyl tail interact to produce the various phenomenological states. Both wild-type and tailless behaviors can be replicated using Monte Carlo computer simulations based on this model.
    MeSH term(s) DNA Repair ; Electrophysiology ; Gene Deletion ; Ions ; Models, Biological ; Monte Carlo Method ; Mutation ; Plasmids ; Potassium/metabolism ; Potassium Channels/chemistry ; Protein Structure, Tertiary ; Saccharomyces cerevisiae/metabolism ; Saccharomyces cerevisiae Proteins
    Chemical Substances Ions ; Potassium Channels ; Saccharomyces cerevisiae Proteins ; TOK1 protein, S cerevisiae ; Potassium (RWP5GA015D)
    Language English
    Publishing date 2002-02
    Publishing country United States
    Document type Journal Article ; Research Support, U.S. Gov't, P.H.S.
    ZDB-ID 218078-9
    ISSN 1542-0086 ; 0006-3495
    ISSN (online) 1542-0086
    ISSN 0006-3495
    DOI 10.1016/S0006-3495(02)75440-4
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  8. Article ; Online: Lipid perturbations sensitize osmotic down-shock activated Ca2+ influx, a yeast "deletome" analysis.

    Loukin, Stephen H / Kung, Ching / Saimi, Yoshiro

    FASEB journal : official publication of the Federation of American Societies for Experimental Biology

    2007  Volume 21, Issue 8, Page(s) 1813–1820

    Abstract: Osmotic down shock causes an immediate influx of Ca2+ in yeast, likely through a membrane stretch-sensitive channel. To see how this channel is constituted and regulated, we screened the collection of 4,906 yeast gene deletants for major changes in this ... ...

    Abstract Osmotic down shock causes an immediate influx of Ca2+ in yeast, likely through a membrane stretch-sensitive channel. To see how this channel is constituted and regulated, we screened the collection of 4,906 yeast gene deletants for major changes in this response by luminomtery. We discovered deletants that responded very strongly to much milder down shocks than wild-type required, but show little changes in up-shock response. Of all the possibilities (general metabolism, ion distribution, cytoskeleton, cell wall, membrane receptors, etc.), most of the over-responders turned out to be deleted of proteins functioning in the biogenesis of phospholipids, sphingolipids, or ergosterol. Other over-responders are annotated to have vesicular transport defects, traceable to lipid defects in some cases. The deletant lacking the de novo synthesis of phosphatidylcholine, opi3delta, is by far the strongest over-responder. opi3 deletion does not cause non-specific leakage but greatly sensitizes the force-sensing Ca2+-influx mechanism. Choline supplementation normalizes the opi3delta response. Thus, the osmotic-pressure induced stretch force apparently controls channel activities through lipids. This unbiased examination of the yeast genome supports the view that forces intrinsic to the bilayer are determined by the geometry of the lipids and these forces, in turn, govern the activities of proteins embedded therein.
    MeSH term(s) Calcium/metabolism ; Calcium Channels/genetics ; Lipids/biosynthesis ; Lipids/physiology ; Osmotic Pressure ; Phosphatidylcholines/biosynthesis ; Sequence Deletion ; Yeasts
    Chemical Substances Calcium Channels ; Lipids ; Phosphatidylcholines ; Calcium (SY7Q814VUP)
    Language English
    Publishing date 2007-06
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 639186-2
    ISSN 1530-6860 ; 0892-6638
    ISSN (online) 1530-6860
    ISSN 0892-6638
    DOI 10.1096/fj.06-7898com
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  9. Article: Lipid perturbations sensitize osmotic down-shock activated Ca²⁺ influx, a yeast "deletome" analysis

    Loukin, Stephen H / Kung, Ching / Saimi, Yoshiro

    FASEB journal. 2007 June, v. 21, no. 8

    2007  

    Abstract: ... govern the activities of proteins embedded therein.--Loukin, S. H, Kung, C., Saimi, Y. Lipid ...

    Abstract Osmotic down shock causes an immediate influx of Ca²⁺ in yeast, likely through a membrane stretch-sensitive channel. To see how this channel is constituted and regulated, we screened the collection of 4,906 yeast gene deletants for major changes in this response by luminomtery. We discovered deletants that responded very strongly to much milder down shocks than wild-type required, but show little changes in up-shock response. Of all the possibilities (general metabolism, ion distribution, cytoskeleton, cell wall, membrane receptors, etc.), most of the over-responders turned out to be deleted of proteins functioning in the biogenesis of phospholipids, sphingolipids, or ergosterol. Other over-responders are annotated to have vesicular transport defects, traceable to lipid defects in some cases. The deletant lacking the de novo synthesis of phosphatidylcholine, opi3Δ, is by far the strongest over-responder. opi3 deletion does not cause non-specific leakage but greatly sensitizes the force-sensing Ca²⁺-influx mechanism. Choline supplementation normalizes the opi3Δ response. Thus, the osmotic-pressure induced stretch force apparently controls channel activities through lipids. This unbiased examination of the yeast genome supports the view that forces intrinsic to the bilayer are determined by the geometry of the lipids and these forces, in turn, govern the activities of proteins embedded therein.--Loukin, S. H, Kung, C., Saimi, Y. Lipid perturbations sensitize osmotic down-shock activated Ca²⁺ influx, a yeast "deletome" analysis.
    Language English
    Dates of publication 2007-06
    Size p. 1813-1820.
    Publishing place The Federation of American Societies for Experimental Biology
    Document type Article
    ZDB-ID 639186-2
    ISSN 1530-6860 ; 0892-6638
    ISSN (online) 1530-6860
    ISSN 0892-6638
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  10. Article ; Online: The use of yeast to understand TRP-channel mechanosensitivity.

    Su, Zhenwei / Zhou, Xinliang / Loukin, Stephen H / Haynes, W John / Saimi, Yoshiro / Kung, Ching

    Pflugers Archiv : European journal of physiology

    2009  Volume 458, Issue 5, Page(s) 861–867

    Abstract: Mechanosensitive (MS) ion channels likely underlie myriad force-sensing processes, from basic osmotic regulation to specified sensations of animal hearing and touch. Albeit important, the molecular identities of many eukaryotic MS channels remain elusive, ...

    Abstract Mechanosensitive (MS) ion channels likely underlie myriad force-sensing processes, from basic osmotic regulation to specified sensations of animal hearing and touch. Albeit important, the molecular identities of many eukaryotic MS channels remain elusive, let alone their working mechanisms. This is in stark contrast to our advanced knowledge on voltage- or ligand-sensitive channels. Several members of transient receptor potential (TRP) ion channel family have been implicated to function in mechanosensation and are recognized as promising candidate MS channels. The yeast TRP homolog, TRPY1, is clearly a first-line force transducer. It can be activated by hypertonic shock in vivo and by membrane stretch force in excised patches under patch clamp, making it a useful model for understanding TRP channel mechanosensitivity in general. TRPY1 offers two additional research advantages: (1) It has a large ( approximately 300 pS) unitary conductance and therefore a favorable S/N ratio. (2) Budding yeast allows convenient and efficient genetic and molecular manipulations. In this review, we focus on the current research of TRPY1 and discuss its prospect. We also describe the use of yeast as a system to express and characterize animal TRP channels.
    MeSH term(s) Animals ; Electrophysiological Phenomena/physiology ; Humans ; Ion Channel Gating/physiology ; Mechanotransduction, Cellular/physiology ; Saccharomyces cerevisiae/physiology ; Saccharomyces cerevisiae Proteins/physiology ; Transient Receptor Potential Channels/physiology
    Chemical Substances Saccharomyces cerevisiae Proteins ; Transient Receptor Potential Channels
    Language English
    Publishing date 2009-05-22
    Publishing country Germany
    Document type Journal Article ; Review
    ZDB-ID 6380-0
    ISSN 1432-2013 ; 0031-6768
    ISSN (online) 1432-2013
    ISSN 0031-6768
    DOI 10.1007/s00424-009-0680-0
    Database MEDical Literature Analysis and Retrieval System OnLINE

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