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Sensitisation of TRPV4 by PAR2 is independent of intracellular calcium signalling and can be mediated by the biased agonist neutrophil elastase

  • Ion channels, receptors and transporters
  • Published:
Pflügers Archiv - European Journal of Physiology Aims and scope Submit manuscript

An Erratum to this article was published on 07 April 2017

Abstract

Proteolytic activation of protease-activated receptor 2 (PAR2) may represent a major mechanism of regulating the transient receptor potential vanilloid 4 (TRPV4) non-selective cation channel in pathophysiological conditions associated with protease activation (e.g. during inflammation). To provide electrophysiological evidence for PAR2-mediated TRPV4 regulation, we characterised the properties of human TRPV4 heterologously expressed in Xenopus laevis oocytes in the presence and absence of co-expressed human PAR2. In outside-out patches from TRPV4 expressing oocytes, we detected single-channel activity typical for TRPV4 with a single-channel conductance of about 100 pS for outward and 55 pS for inward currents. The synthetic TRPV4 activator GSK1016790A stimulated TRPV4 mainly by converting previously silent channels into active channels with an open probability of nearly one. In oocytes co-expressing TRPV4 and PAR2, PAR2 activation by trypsin or by specific PAR2 agonist SLIGRL-NH2 potentiated the GSK1016790A-stimulated TRPV4 whole-cell currents several fold, indicative of channel sensitisation. Pre-incubation of oocytes with the calcium chelator 1,2-bis(2-aminophenoxy)ethane-N,N,N′,N′-tetraacetic acid (BAPTA)-AM did not reduce the stimulatory effect of PAR2 activation on TRPV4, which indicates that the effect is independent of intracellular calcium signalling. Neutrophil elastase, a biased agonist of PAR2 that does not induce intracellular calcium signalling, also caused a PAR2-dependent sensitisation of TRPV4. The Rho-kinase inhibitor Y27362 abolished elastase-stimulated sensitisation of TRPV4, which indicates that Rho-kinase signalling plays a critical role in PAR2-mediated TRPV4 sensitisation by the biased agonist neutrophil elastase. During acute inflammation, neutrophil elastase may sensitise TRPV4 by a mechanism involving biased agonism of PAR2 and activation of Rho-kinase.

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Abbreviations

TRPV4:

Transient receptor potential vanilloid 4

PAR2 :

Protease-activated receptor 2

GPCR:

G protein-coupled receptor

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Acknowledgments

The expert technical assistance of Ralf Rinke is gratefully acknowledged. This study was supported by a PhD fellowship from the Bayerische Forschungsstiftung (S.S.) and by NHMRC grants 63303, 1031886, 1046860 and 1049682 and Monash University (N.W.B., P.M.).

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Authors and Affiliations

  1. Institut für Zelluläre und Molekulare Physiologie, Friedrich-Alexander-Universität Erlangen-Nürnberg, Waldstr. 6, 91054, Erlangen, Germany

    Silvia Sostegni, Alexei Diakov, Christoph Korbmacher & Silke Haerteis

  2. Health Innovations Research Institute, School of Medical Sciences, RMIT University, Bundoora, VIC, 3083, Australia

    Peter McIntyre

  3. Monash Institute of Pharmaceutical Sciences, 381 Royal Parade, Parkville, VIC, 3052, Australia

    Nigel Bunnett

  4. Department of Pharmacology and Therapeutics, University of Melbourne, 1-100 Grattan Street, Parkville, VIC, 3010, Australia

    Nigel Bunnett

Authors
  1. Silvia Sostegni
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  2. Alexei Diakov
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  3. Peter McIntyre
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  4. Nigel Bunnett
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  5. Christoph Korbmacher
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  6. Silke Haerteis
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Corresponding author

Correspondence to Christoph Korbmacher.

Additional information

An erratum to this article is available at http://dx.doi.org/10.1007/s00424-017-1973-3.

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Sostegni, S., Diakov, A., McIntyre, P. et al. Sensitisation of TRPV4 by PAR2 is independent of intracellular calcium signalling and can be mediated by the biased agonist neutrophil elastase. Pflugers Arch - Eur J Physiol 467, 687–701 (2015). https://doi.org/10.1007/s00424-014-1539-6

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  • DOI: https://doi.org/10.1007/s00424-014-1539-6

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