Single point mutations of aromatic residues in transmembrane helices 5 and -6 differentially affect TRPV4 activation by 4α-PDD and hypotonicity: implications for the role of the pore region in regulating TRPV4 activity

Thomas Kjær Klausen; Annelies Janssens; Jean Prenen; Grzegorz Owsianik; Else Kay Hoffmann; Stine Helene Falsig Pedersen; Bernd Nilius

doi:10.1016/j.ceca.2013.11.001

Single point mutations of aromatic residues in transmembrane helices 5 and -6 differentially affect TRPV4 activation by 4α-PDD and hypotonicity: implications for the role of the pore region in regulating TRPV4 activity

Thomas Kjær Klausen, Annelies Janssens, Jean Prenen, Grzegorz Owsianik, Else Kay Hoffmann, Stine Helene Falsig Pedersen, Bernd Nilius

Cellebiologi og Fysiologi

5 Citationer (Scopus)

Abstract

The importance of the TRPV4 channel for human physiology has been highlighted in recent years with the identification of an increasing number of hereditary diseases associated with mutations of this channel. However, the functional understanding of TRPV4 associated pathologies remains a puzzle due to incomplete understanding of the polymodal regulation of TRPV4 channels and lack of insight into the structure-function relationship of the channel. In this work, we identified a series of highly conserved aromatic residues in transmembrane (TM) helices 5-6 with profound importance for TRPV4 activity. Substituting F617, Y621 or F624 in TM5 with leucine reduced channel sensitivity to the agonist 4α-PDD and heat, yet two of these mutants - F617L and Y621L - showed increased activation in response to cell swelling. In TM6, a Y702L mutation significantly reduced sensitivity to all of the above stimuli. In conclusion, we have identified residues in TM5-6 which differentially affect heat and agonist activation, and we have demonstrated distinct activation pathways for 4α-PDD and osmolarity.

Originalsprog	Engelsk
Tidsskrift	Cell Calcium
Vol/bind	55
Udgave nummer	1
Sider (fra-til)	38-47
Antal sider	10
ISSN	0143-4160
DOI	https://doi.org/10.1016/j.ceca.2013.11.001
Status	Udgivet - jan. 2014

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10.1016/j.ceca.2013.11.001

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Citationsformater

Klausen, T. K., Janssens, A., Prenen, J., Owsianik, G., Hoffmann, E. K., Pedersen, S. H. F., & Nilius, B. (2014). Single point mutations of aromatic residues in transmembrane helices 5 and -6 differentially affect TRPV4 activation by 4α-PDD and hypotonicity: implications for the role of the pore region in regulating TRPV4 activity. Cell Calcium, 55(1), 38-47. https://doi.org/10.1016/j.ceca.2013.11.001

Single point mutations of aromatic residues in transmembrane helices 5 and -6 differentially affect TRPV4 activation by 4α-PDD and hypotonicity : implications for the role of the pore region in regulating TRPV4 activity. / Klausen, Thomas Kjær; Janssens, Annelies; Prenen, Jean et al.

I: Cell Calcium, Bind 55, Nr. 1, 01.2014, s. 38-47.

Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › peer review

Klausen, TK, Janssens, A, Prenen, J, Owsianik, G, Hoffmann, EK, Pedersen, SHF & Nilius, B 2014, 'Single point mutations of aromatic residues in transmembrane helices 5 and -6 differentially affect TRPV4 activation by 4α-PDD and hypotonicity: implications for the role of the pore region in regulating TRPV4 activity', Cell Calcium, bind 55, nr. 1, s. 38-47. https://doi.org/10.1016/j.ceca.2013.11.001

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title = "Single point mutations of aromatic residues in transmembrane helices 5 and -6 differentially affect TRPV4 activation by 4α-PDD and hypotonicity: implications for the role of the pore region in regulating TRPV4 activity",

abstract = "The importance of the TRPV4 channel for human physiology has been highlighted in recent years with the identification of an increasing number of hereditary diseases associated with mutations of this channel. However, the functional understanding of TRPV4 associated pathologies remains a puzzle due to incomplete understanding of the polymodal regulation of TRPV4 channels and lack of insight into the structure-function relationship of the channel. In this work, we identified a series of highly conserved aromatic residues in transmembrane (TM) helices 5-6 with profound importance for TRPV4 activity. Substituting F617, Y621 or F624 in TM5 with leucine reduced channel sensitivity to the agonist 4α-PDD and heat, yet two of these mutants - F617L and Y621L - showed increased activation in response to cell swelling. In TM6, a Y702L mutation significantly reduced sensitivity to all of the above stimuli. In conclusion, we have identified residues in TM5-6 which differentially affect heat and agonist activation, and we have demonstrated distinct activation pathways for 4α-PDD and osmolarity.",

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T1 - Single point mutations of aromatic residues in transmembrane helices 5 and -6 differentially affect TRPV4 activation by 4α-PDD and hypotonicity

T2 - implications for the role of the pore region in regulating TRPV4 activity

AU - Klausen, Thomas Kjær

AU - Janssens, Annelies

AU - Prenen, Jean

AU - Owsianik, Grzegorz

AU - Hoffmann, Else Kay

AU - Pedersen, Stine Helene Falsig

AU - Nilius, Bernd

PY - 2014/1

Y1 - 2014/1

N2 - The importance of the TRPV4 channel for human physiology has been highlighted in recent years with the identification of an increasing number of hereditary diseases associated with mutations of this channel. However, the functional understanding of TRPV4 associated pathologies remains a puzzle due to incomplete understanding of the polymodal regulation of TRPV4 channels and lack of insight into the structure-function relationship of the channel. In this work, we identified a series of highly conserved aromatic residues in transmembrane (TM) helices 5-6 with profound importance for TRPV4 activity. Substituting F617, Y621 or F624 in TM5 with leucine reduced channel sensitivity to the agonist 4α-PDD and heat, yet two of these mutants - F617L and Y621L - showed increased activation in response to cell swelling. In TM6, a Y702L mutation significantly reduced sensitivity to all of the above stimuli. In conclusion, we have identified residues in TM5-6 which differentially affect heat and agonist activation, and we have demonstrated distinct activation pathways for 4α-PDD and osmolarity.

AB - The importance of the TRPV4 channel for human physiology has been highlighted in recent years with the identification of an increasing number of hereditary diseases associated with mutations of this channel. However, the functional understanding of TRPV4 associated pathologies remains a puzzle due to incomplete understanding of the polymodal regulation of TRPV4 channels and lack of insight into the structure-function relationship of the channel. In this work, we identified a series of highly conserved aromatic residues in transmembrane (TM) helices 5-6 with profound importance for TRPV4 activity. Substituting F617, Y621 or F624 in TM5 with leucine reduced channel sensitivity to the agonist 4α-PDD and heat, yet two of these mutants - F617L and Y621L - showed increased activation in response to cell swelling. In TM6, a Y702L mutation significantly reduced sensitivity to all of the above stimuli. In conclusion, we have identified residues in TM5-6 which differentially affect heat and agonist activation, and we have demonstrated distinct activation pathways for 4α-PDD and osmolarity.

U2 - 10.1016/j.ceca.2013.11.001

DO - 10.1016/j.ceca.2013.11.001

M3 - Journal article

C2 - 24342753

SN - 0143-4160

VL - 55

SP - 38

EP - 47

JO - Cell Calcium

JF - Cell Calcium

IS - 1

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