Response to mechanical stress is mediated by the TRPA channel painless in the Drosophila 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.
Sénatore
Sébastien
S
Institut de Biologie du Développement de Marseille-Luminy, UMR-CNRS 6216, Université de la Méditerranée, Marseille, France.
Rami Reddy
Vatrapu
V
Sémériva
Michel
M
Perrin
Laurent
L
Lalevée
Nathalie
N
D000818:Animals; D029721:Drosophila Proteins / Q000378:metabolism*; D004331:Drosophila melanogaster / Q000235:genetics / Q000378:metabolism*; D055785:Gene Knockdown Techniques; D005820:Genetic Testing; D015640:Ion Channel Gating; D007473:Ion Channels / Q000378:metabolism*; D007814:Larva / Q000378:metabolism; D040542:Mechanotransduction, Cellular / Q000235:genetics; D009206:Myocardium / Q000378:metabolism* / Q000473:pathology*; D013314:Stress, Mechanical; D013696:Temperature
D029721:Drosophila Proteins; D007473:Ion Channels; C474592:pain protein, Drosophila
Nat Rev Neurosci. 2007 Jul;8(7):510-21
17585304
Can J Physiol Pharmacol. 2005 Mar;83(3):215-42
15870837
Nat Rev Mol Cell Biol. 2009 Jan;10(1):63-73
19197333
Nat Rev Mol Cell Biol. 2009 Jan;10(1):53-62
19197332
Cell. 2009 Oct 16;139(2):267-84
19837031
Pflugers Arch. 2008 Mar;455(6):1097-103
17957383
Nature. 2008 Jul 10;454(7201):217-20
18548007
Dev Biol. 2009 Apr 15;328(2):483-92
19233157
J Gen Physiol. 1963 Mar;46:803-21
13932039
Proc Natl Acad Sci U S A. 1986 Nov;83(21):8415-9
2430288
Curr Opin Genet Dev. 2009 Oct;19(5):518-25
19717296
Nat Neurosci. 2007 May;10(5):568-77
17450139
J Neurosci. 1995 Sep;15(9):6085-93
7666192
Fly (Austin). 2007 Mar-Apr;1(2):59-67
18820463
Circ Res. 2009 Apr 24;104(8):987-94
19299646
Cardiovasc Res. 1996 Jul;32(1):38-43
8776401
Curr Biol. 2006 Aug 8;16(15):1502-8
16890525
Dev Neurobiol. 2008 Feb 15;68(3):309-16
18044732
J Neurosci. 1991 Oct;11(10):3047-59
1658244
Annu Rev Physiol. 2006;68:619-47
16460286
Biophys J. 2006 Jan 1;90(1):381-9
16214862
Cell. 2003 Apr 18;113(2):261-73
12705873
Nat Chem Biol. 2005 Jul;1(2):85-92
16408004
Prog Biophys Mol Biol. 2008 Jun-Jul;97(2-3):180-95
18343483
Circ Res. 2006 Jul 21;99(2):119-31
16857972
Gene. 2004 Nov 10;342(1):1-11
15527959
J Neurosci. 2008 Oct 1;28(40):10102-10
18829968
Pflugers Arch. 2008 Jun;456(3):529-40
18183414
Biotechniques. 2009 Feb;46(2):101-13
19317655
Proc Natl Acad Sci U S A. 2006 Oct 31;103(44):16586-91
17056714
Nature. 2007 Nov 8;450(7167):294-8
17994098
J Neurosci. 2008 Oct 1;28(40):9929-38
18829951
Nat Rev Mol Cell Biol. 2009 Jan;10(1):44-52
19197331
Prog Biophys Mol Biol. 1999;71(1):91-138
10070213
J Neurogenet. 1998 Jan;12(1):1-24
9666898
Dev Cell. 2006 Jan;10(1):11-20
16399074
Development. 2005 Dec;132(23):5283-93
16284119
Dev Biol. 2004 Mar 15;267(2):536-47
15013812
Curr Biol. 2006 May 23;16(10):1034-40
16647259
Development. 1993 Jun;118(2):401-15
8223268
Proc Natl Acad Sci U S A. 2007 Feb 27;104(9):3312-7
17360644
Ann N Y Acad Sci. 1965 Sep 8;127(1):84-99
5217297
Annu Rev Biochem. 2007;76:387-417
17579562
Nature. 2004 Dec 9;432(7018):723-30
15483558
Proc Natl Acad Sci U S A. 2007 Mar 6;104(10):3943-8
17360457
Cell. 2009 Oct 30;139(3):587-96
19879844