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Response to Mechanical Stress Is Mediated by the TRPA Channel Painless in the Heart


Mechanotransduction modulates cellular functions as diverse as migration, proliferation, differentiation, and apoptosis. It is crucial for organ development and homeostasis and leads to pathologies when defective. However, despite considerable efforts made in the past, the molecular basis of mechanotransduction remains poorly understood. Here, we have investigated the genetic basis of mechanotransduction in Drosophila. We show that the fly heart senses and responds to mechanical forces by regulating cardiac activity. In particular, pauses in heart activity are observed under acute mechanical constraints in vivo. We further confirm by a variety of in situ tests that these cardiac arrests constitute the biological force-induced response. In order to identify molecular components of the mechanotransduction pathway, we carried out a genetic screen based on the dependence of cardiac activity upon mechanical constraints and identified Painless, a TRPA channel. We observe a clear absence of in vivo cardiac arrest following inactivation of painless and further demonstrate that painless is autonomously required in the heart to mediate the response to mechanical stress. Furthermore, direct activation of Painless is sufficient to produce pauses in heartbeat, mimicking the pressure-induced response. Painless thus constitutes part of a mechanosensitive pathway that adjusts cardiac muscle activity to mechanical constraints. This constitutes the first in vivo demonstration that a TRPA channel can mediate cardiac mechanotransduction. Furthermore, by establishing a high-throughput system to identify the molecular players involved in mechanotransduction in the cardiovascular system, our study paves the way for understanding the mechanisms underlying a mechanotransduction pathway.


Vyšlo v časopise: Response to Mechanical Stress Is Mediated by the TRPA Channel Painless in the Heart. PLoS Genet 6(9): e32767. doi:10.1371/journal.pgen.1001088
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.pgen.1001088

Souhrn

Mechanotransduction modulates cellular functions as diverse as migration, proliferation, differentiation, and apoptosis. It is crucial for organ development and homeostasis and leads to pathologies when defective. However, despite considerable efforts made in the past, the molecular basis of mechanotransduction remains poorly understood. Here, we have investigated the genetic basis of mechanotransduction in Drosophila. We show that the fly heart senses and responds to mechanical forces by regulating cardiac activity. In particular, pauses in heart activity are observed under acute mechanical constraints in vivo. We further confirm by a variety of in situ tests that these cardiac arrests constitute the biological force-induced response. In order to identify molecular components of the mechanotransduction pathway, we carried out a genetic screen based on the dependence of cardiac activity upon mechanical constraints and identified Painless, a TRPA channel. We observe a clear absence of in vivo cardiac arrest following inactivation of painless and further demonstrate that painless is autonomously required in the heart to mediate the response to mechanical stress. Furthermore, direct activation of Painless is sufficient to produce pauses in heartbeat, mimicking the pressure-induced response. Painless thus constitutes part of a mechanosensitive pathway that adjusts cardiac muscle activity to mechanical constraints. This constitutes the first in vivo demonstration that a TRPA channel can mediate cardiac mechanotransduction. Furthermore, by establishing a high-throughput system to identify the molecular players involved in mechanotransduction in the cardiovascular system, our study paves the way for understanding the mechanisms underlying a mechanotransduction pathway.


Zdroje

1. OrrAW

HelmkeBP

BlackmanBR

SchwartzMA

2006 Mechanisms of mechanotransduction. Dev Cell 10 11 20

2. JaaloukDE

LammerdingJ

2009 Mechanotransduction gone awry. Nat Rev Mol Cell Biol 10 63 73

3. BasbaumAI

BautistaDM

ScherrerG

JuliusD

2009 Cellular and molecular mechanisms of pain. Cell 139 267 284

4. ChalfieM

2009 Neurosensory mechanotransduction. Nat Rev Mol Cell Biol 10 44 52

5. FolgeringJH

Sharif-NaeiniR

DedmanA

PatelA

DelmasP

2008 Molecular basis of the mammalian pressure-sensitive ion channels: focus on vascular mechanotransduction. Prog Biophys Mol Biol 97 180 195

6. HahnC

SchwartzMA

2009 Mechanotransduction in vascular physiology and atherogenesis. Nat Rev Mol Cell Biol 10 53 62

7. Sharif-NaeiniR

FolgeringJH

BichetD

DupratF

LauritzenI

2009 Polycystin-1 and -2 dosage regulates pressure sensing. Cell 139 587 596

8. KohlP

HunterP

NobleD

1999 Stretch-induced changes in heart rate and rhythm: clinical observations, experiments and mathematical models. Prog Biophys Mol Biol 71 91 138

9. MonierB

TevyM

PerrinL

CapovillaM

SémérivaM

2007 Downstream of Homeotic genes: in the heart of Hox function. Fly 1 59 67

10. MedioniC

SenatoreS

SalmandPA

LaleveeN

PerrinL

2009 The fabulous destiny of the Drosophila heart. Curr Opin Genet Dev 19 518 525

11. LaleveeN

MonierB

SenatoreS

PerrinL

SemerivaM

2006 Control of cardiac rhythm by ORK1, a Drosophila two-pore domain potassium channel. Curr Biol 16 1502 1508

12. MillerTA

1974 Electrophysiology of the insect heart. The physiology of insecta Morris Rockstein, 2nd edition Academic Press V 169 200

13. DixitR

VijayraghavanK

BateM

2008 Hox genes and the regulation of movement in Drosophila. Dev Neurobiol 68 309 316

14. BuechlingT

AkasakaT

VoglerG

Ruiz-LozanoP

OcorrK

2009 Non-autonomous modulation of heart rhythm, contractility and morphology in adult fruit flies. Dev Biol 328 483 492

15. MonierB

AstierM

SemerivaM

PerrinL

2005 Steroid-dependent modification of Hox function drives myocyte reprogramming in the Drosophila heart. Development 132 5283 5293

16. SpassovaMA

HewavitharanaT

XuW

SoboloffJ

GillDL

2006 A common mechanism underlies stretch activation and receptor activation of TRPC6 channels. Proc Natl Acad Sci U S A 103 16586 16591

17. McCannFV

1963 Electrophysiology of an insect heart. J Gen Physiol 46 803 821

18. McCannFV

1965 Unique properties of the moth myocardium. Ann N Y Acad Sci 127 84 99

19. GielowML

GuGG

SinghS

1995 Resolution and pharmacological analysis of the voltage-dependent calcium channels of Drosophila larval muscles. J Neurosci 15 6085 6093

20. LeungHT

ByerlyL

1991 Characterization of single calcium channels in Drosophila embryonic nerve and muscle cells. J Neurosci 11 3047 3059

21. JohnsonE

RingoJ

BrayN

DowseH

1998 Genetic and pharmacological identification of ion channels central to the Drosophila cardiac pacemaker. J Neurogenet 12 1 24

22. BrandAH

PerrimonN

1993 Targeted gene expression as a means of altering cell fates and generating dominant phenotypes. Development 118 401 415

23. Al-AnziB

TraceyWDJr

BenzerS

2006 Response of Drosophila to wasabi is mediated by painless, the fly homolog of mammalian TRPA1/ANKTM1. Curr Biol 16 1034 1040

24. TraceyWDJr

WilsonRI

LaurentG

BenzerS

2003 painless, a Drosophila gene essential for nociception. Cell 113 261 273

25. SokabeT

TsujiuchiS

KadowakiT

TominagaM

2008 Drosophila painless is a Ca2+-requiring channel activated by noxious heat. J Neurosci 28 9929 9938

26. ChristensenAP

CoreyDP

2007 TRP channels in mechanosensation: direct or indirect activation? Nat Rev Neurosci 8 510 521

27. RamseyIS

DellingM

ClaphamDE

2006 An introduction to TRP channels. Annu Rev Physiol 68 619 647

28. VenkatachalamK

MontellC

2007 TRP channels. Annu Rev Biochem 76 387 417

29. VoetsT

TalaveraK

OwsianikG

NiliusB

2005 Sensing with TRP channels. Nat Chem Biol 1 85 92

30. InoueR

JensenLJ

ShiJ

MoritaH

NishidaM

2006 Transient receptor potential channels in cardiovascular function and disease. Circ Res 99 119 131

31. Sharif-NaeiniR

DedmanA

FolgeringJH

DupratF

PatelA

2008 TRP channels and mechanosensory transduction: insights into the arterial myogenic response. Pflugers Arch

32. GottliebP

FolgeringJ

MarotoR

RasoA

WoodTG

2008 Revisiting TRPC1 and TRPC6 mechanosensitivity. Pflugers Arch 455 1097 1103

33. CoreyDP

Garcia-AnoverosJ

HoltJR

KwanKY

LinSY

2004 TRPA1 is a candidate for the mechanosensitive transduction channel of vertebrate hair cells. Nature 432 723 730

34. KindtKS

ViswanathV

MacphersonL

QuastK

HuH

2007 Caenorhabditis elegans TRPA-1 functions in mechanosensation. Nat Neurosci 10 568 577

35. ProberDA

ZimmermanS

MyersBR

McDermottBMJr

KimSH

2008 Zebrafish TRPA1 channels are required for chemosensation but not for thermosensation or mechanosensory hair cell function. J Neurosci 28 10102 10110

36. EarleyS

GonzalesAL

CrnichR

2009 Endothelium-dependent cerebral artery dilation mediated by TRPA1 and Ca2+-Activated K+ channels. Circ Res 104 987 994

37. ThorneloeKS

NelsonMT

2005 Ion channels in smooth muscle: regulators of intracellular calcium and contractility. Can J Physiol Pharmacol 83 215 242

38. BretteF

SalleL

OrchardCH

2006 Quantification of calcium entry at the T-tubules and surface membrane in rat ventricular myocytes. Biophys J 90 381 389

39. TaggartP

1996 Mechano-electric feedback in the human heart. Cardiovasc Res 32 38 43

40. CrippsRM

LovatoTL

OlsonEN

2004 Positive autoregulation of the Myocyte enhancer factor-2 myogenic control gene during somatic muscle development in Drosophila. Dev Biol 267 536 547

41. BierE

BodmerR

2004 Drosophila, an emerging model for cardiac disease. Gene 342 1 11

42. OcorrK

ReevesNL

WessellsRJ

FinkM

ChenHS

2007 KCNQ potassium channel mutations cause cardiac arrhythmias in Drosophila that mimic the effects of aging. Proc Natl Acad Sci U S A 104 3943 3948

43. ElkinsT

GanetzkyB

WuCF

1986 A Drosophila mutation that eliminates a calcium-dependent potassium current. Proc Natl Acad Sci U S A 83 8415 8419

44. HamadaFN

RosenzweigM

KangK

PulverSR

GhezziA

2008 An internal thermal sensor controlling temperature preference in Drosophila. Nature 454 217 220

45. LiuL

LiY

WangR

YinC

DongQ

2007 Drosophila hygrosensation requires the TRP channels water witch and nanchung. Nature 450 294 298

46. BischofJ

MaedaRK

HedigerM

KarchF

BaslerK

2007 An optimized transgenesis system for Drosophila using germ-line-specific phiC31 integrases. Proc Natl Acad Sci U S A 104 3312 3317

47. FinkM

Callol-MassotC

ChuA

Ruiz-LozanoP

BelmonteJC

2009 A new method for detection and quantification of heartbeat parameters in Drosophila, zebrafish, and embryonic mouse hearts. Biotechniques 46 101 113

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Genetika Reprodukčná medicína

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