Elsevier

Pharmacology & Therapeutics

Volume 123, Issue 3, September 2009, Pages 371-385
Pharmacology & Therapeutics

Associate editor: M. Endoh
Mechanosensitive TRP channels in cardiovascular pathophysiology

https://doi.org/10.1016/j.pharmthera.2009.05.009Get rights and content

Abstract

Transient receptor potential (TRP) proteins constitute a large non-voltage-gated cation channel superfamily, activated polymodally by various physicochemical stimuli, and are implicated in a variety of cellular functions. Known activators for TRP include not only chemical stimuli such as receptor stimulation, increased acidity and pungent/cooling agents, but temperature change and various forms of mechanical stimuli such as osmotic stress, membrane stretch, and shear force. Recent investigations have revealed that at least ten mammalian TRPs exhibit mechanosensitivity (TRPC1, 5, 6; TRPV1, 2, 4; TRPM3, 7; TRPA1; TRPP2), but the mechanisms underlying it appear considerably divergent and complex. The proposed mechanisms are associated with lipid bilayer mechanics, specialized force-transducing structures, biochemical reactions, membrane trafficking and transcriptional regulation. Many of mechanosensitive (MS)-TRP channel likely undergo multiple regulations via these mechanisms. In the cardiovascular system in which hemodynamic forces constantly operate, the impact of mechanical stress may be particularly significant. Extensive morphological and functional studies have indicated that several MS-TRP channels are expressed in cardiac muscle, vascular smooth muscle, endothelium and vasosensory neurons, each differentially contributing to cardiovascular (CV) functions. To further complexity, the recent evidence suggests that mechanical stress may synergize with neurohormonal mechanisms thereby amplifying otherwise marginal responses. Furthermore, the currently available data suggest that MS-TRP channels may be involved in CV pathophysiology such as cardiac arrhythmia, cardiac hypertrophy/myopathy, hypertension and aneurysms. This review will overview currently known mechanisms for mechanical activation/modulation of TRPs and possible connections of MS-TRP channels to CV disorders.

Introduction

The blood pressure is maintained in an optimal range to keep a sufficient blood flow to peripheral tissues and organs to deliver oxygen and nutrients or transport waste products away. To do so, the pumping function of the heart, resistance and distensibility of blood vessels, and water and salt handing of the kidney are elaborately controlled by various mechanisms that can sense moment-to-moment changes in the metabolic demand of peripheral tissues and hemodynamics of whole and local circulations thereby exerting acute and long-term feedback regulations (Guyton & Hall, 2005).

In general, these regulations are thought to occur via cardiovascular actions of neurohormonal factors; neurotransmitters released from autonomic nerves; vasoactive hormones derived from endocrine organs; vasoactive substances paracrinely or autocrinely secreted from endothelial cells (ECs), vascular smooth muscle cells (VSMCs), and migrating blood cells. However, recent evidence has increasingly disclosed that mechanical stress, which constantly operates in circulations as the blood pressure/flow and osmotic change or is generated by deformation of the heart and blood vessels during contraction and relaxation, may also actively participate in short- and long-term regulations of cardiovascular (CV) functions and associated disorders.

These are exemplified by physiological responses known as e.g. myogenic response, baroreceptor reflex, shear stress-induced release of endothelium-derived factors, and stretch-induced release of renin and atrial natriuretic peptide, and by pathological conditions arising from complex neurohormonal/mechanical interactions manifested as hypertension, arteriosclerosis, vasospasm, and cardiac hypertrophy (Davis and Hill, 1999, Heineke and Molkentin, 2006, Davis, 2009). However, none of them has yet been fully understood at the molecular level.

The mechanisms by which a cell can sense and transduce mechanical stimuli (termed ‘mechanosensation’ and ‘mechanotransduction’ respectively) are deemed to have originated in a very early stage of evolution. In bacteria and archaea, mechanosensitive (MS) ion channels already exist, which open in response to osmotic reduction to protect cells by releasing the osmolites (Martinac & Kloda, 2003). Reconstitution of these MS channels in artificial liposome revealed that they are directly gated in a manner dependent on lipid bilayer tension (‘bilayer-dependent mechanism’) (Sukharev et al., 1993, Corry and Martinac, 2008; Fig. 1A).

In higher organisms (eukaryotes), a refined submembranous scaffold, i.e. actin cytoskeleton, is developed to support the plasma membrane and tether transmembrane proteins. The intracellular network of cytoskeleton further forms a specialized framework interconnected with extracellular matrix via integrins. It has been proposed that this cellular framework may serve as a pre-tensed architecture with tensile and compressive elements linking with downstream adaptor/signaling proteins at focal contacts and converting external forces into biochemical information (‘tensegrity’ model; Ingber, 2008). There are indeed a wealth of evidence suggesting that various forms of mechanical stresses can activate biochemical cascades including G-proteins, adenylyl cyclase, phospholipase C (PLC), phospholipase A2 (PLA2), mitogen-activated protein kinases, tyrosine kinases and ion channels (‘mechano-biochemical conversion’; Martinez-Lemus et al., 2003, Hughes-Fulford, 2004; Fig. 2).

In vertebrate audio-vestibular hair cells, there is a special tethered structure called ‘tip-links’ which is believed to transduce the acoustic vibrations or head movements into electrical signals via the strength-dependent deflection (or resultant tension) of elastic stereocilia which activates nonselective cation channels (‘tethered mechanism’; Fig. 1B). A similar tethered mechanism also appears to operate in Drosophila's bristle and nematode's touch sensations (Tavernarakis and Driscoll, 1997, Hamill and Martinac, 2001, Christensen and Corey, 2007).

Thus, it has been speculated that mechanotransduction which had first evolved as MS channels in primitive unicellular cells, was greatly diversified and specialized as the complexity increased in multicellular systems, by adding auxiliary elements to fine-tune or elaborate the means of sensing, transmitting and translating mechanical information to meet variable biological functions. One notable point is, however, that MS channels are ubiquitously found in almost all kinds of cells of extant organisms and appear to avidly participate in their functions. Although the molecular elucidation of MS channels had largely been hampered because of the lack of useful experimental means, recent extensive surveys have led to an exciting discovery of several promising molecular correlates including the DEC/ENaC/ASIC family (Drummond et al., 2008), two-pore domain K+ channels (TREK1, TRAAK; Dedman et al., 2008, Folgering et al., 2008) and transient receptor potential (TRP) cation channel superfamily (Christensen and Corey, 2007, Sharif-Naeini et al., 2008). Amongst these, available information so far strongly suggests that the polymodal activation and high Ca2+- (and -Na+) permeating properties of TRP channels make them particularly attractive to elucidate the divergent functions of MS channels in the living systems.

To increase the readability, this review will attempt first, (1) to briefly outline Ca2+-mobilizing mechanisms regulating CV functions and introduce the general features of TRP channels, and then (2) to recapitulate the mechanisms so far proposed for mechanical activation/modulation of TRP channels (i.e. MS-TRPs), and finally (3) to consider their postulated pathophysiological roles in the CV system (CVS).

Section snippets

The outline of Ca2+-mobilizing mechanisms that regulate CV functions

Calcium ion (Ca2+) has an evolutionarily very old origin as the ubiquitous intracellular messenger that mediates a wide repertoire of cellular functions (Whitfiled, 1995). These include not only acute effects such as muscle contraction, nerve excitation, and secretion, but also slow fundamental processes of self replication, renewal and reorganization associated with cell proliferation, differentiation and programmed cell death (Berridge et al., 1998). The essential importance of Ca2+ in

TRP channel superfamily

Human TRP channels constitute a large non-voltage-gated cation channel superfamily consisting of six families showing distinct activation profiles, i.e. TRPC1-7 (canonical or classical), TRPV1-6 (vanilloid), TRPM1-8 (melastatin), TRPP1-4 (polycystin), TRPML1-3 (mucolipin), and TRPA1 (ankyrin) (Ramsey et al., 2006, Flockerzi, 2007). Although the fine three-dimensional structure has not yet been resolved, the predicted membrane topology of TRP channels indicates six transmembrane (TM) domains

Putative mechanisms proposed for mechanical activation/modulation of transient receptor potential protein

There is substantial evidence that TRP channels may be activated or modulated mechanically. Currently available data suggest that at least, ten mammalian TRPs such as TRPC1, 5, 6, TRPV1, 2, 4, TRPM3, 7, TRPP2 and TRPA1, Drosphophila TRPN1, C. elegans OSM-9 and yeast TRPY1–3 are mechanosensitive, although some of them are questioned for the relevance. The mechanisms for mechanical activation of respective TRP channels have been recently reviewed in great details (Christensen and Corey, 2007,

Pathophysiological implications of mechanosensitive transient receptor potential proteins in CV system

The ubiquitous nature of mechanical forces in CVS raises the possibility that many CV dysfunctions may result from disrupted Ca2+ homeostasis and/or abnormality in Ca2+ handling associated with putative MS-TRP channels distributed in CVS (Table 2). The following part will introduce some of intriguing findings so far reported. Readers interested in physiological roles of MS-TRPs in CVS such as myogenic response are recommended to consult a number of recent reviews (Inoue et al., 2006,

Conclusions

Recent explosion of the research on TRP channels has rapidly broadened our knowledge about their properties, regulations and functions. As an unexpected but exciting result, many of TRP channels have been found to be mechanically activated or modulated. The investigation of mechanisms underlying therein has again revealed the polymodality or promiscuity of respective MS-TRP isoforms. Many of them appear to undergo multiple mechanical regulations associated with lipid bilayer mechanics,

Acknowledgments

This work is supported in part by grants-in-aid to R.I. from the Japan Society for Promotion of Sciences, the Tokyo Biochemical Research Foundation, and the Vehicle Racing Commemorative Foundation.

References (195)

  • FranzM.R. et al.

    Mechano-electrical feedback underlying arrhythmias: the atrial fibrillation case

    Prog Biophys Mol Biol

    (2003)
  • Garcia-EliasA. et al.

    IP3 receptor binds to and sensitizes TRPV4 channel to osmotic stimuli via a calmodulin-binding site

    J Biol Chem

    (2008)
  • GuibertC. et al.

    Voltage-independent calcium influx in smooth muscle

    Prog Biophys Mol Biol

    (2008)
  • HillK. et al.

    TRPA1 is differentially modulated by the amphipathic molecules trinitrophenol and chlorpromazine

    J Biol Chem

    (2007)
  • HillA.J. et al.

    A TRPC-like non-selective cation current activated by alpha 1-adrenoceptors in rat mesenteric artery smooth muscle cells

    Cell Calcium

    (2006)
  • HuH. et al.

    Stretch-activated ion channels in the heart

    J Mol Cell Cardiol

    (1997)
  • IngberD.E.

    Tensegrity-based mechanosensing from macro to micro

    Prog Biophys Mol Biol

    (2008)
  • John HaynesW. et al.

    Indole and other aromatic compounds activate the yeast TRPY1 channel

    FEBS Lett

    (2008)
  • LehtonenJ.Y. et al.

    Phospholipase A2 as a mechanosensor

    Biophys J

    (1995)
  • Alessandri-HaberN. et al.

    Transient receptor potential vanilloid 4 is essential in chemotherapy-induced neuropathic pain in the rat

    J Neurosci

    (2004)
  • AmbudkarI.S.

    Trafficking of TRP channels: determinants of channel function

    Handb Exp Pharmacol

    (2007)
  • BaeY.M. et al.

    Enhancement of receptor-operated cation current and TRPC6 expression in arterial smooth muscle cells of deoxycorticosterone acetate-salt hypertensive rats

    J Hypertens

    (2007)
  • BahnasiY.M. et al.

    Modulation of TRPC5 cation channels by halothane, chloroform and propofol

    Br J Pharmacol

    (2008)
  • BaiC.X. et al.

    Formation of a new receptor-operated channel by heteromeric assembly of TRPP2 and TRPC1 subunits

    EMBO Rep

    (2008)
  • BeechD.J.

    TRPC1: store-operated channel and more

    Pflugers Arch

    (2005)
  • BeechD.J. et al.

    Non-selective cationic channels of smooth muscle and the mammalian homologues of Drosophila TRP

    J Physiol

    (2004)
  • BerridgeM.J. et al.

    Calcium—a life and death signal

    Nature

    (1998)
  • BelusA. et al.

    Streptomycin and intracellular calcium modulate the response of single guinea-pig ventricular myocytes to axial stretch

    J Physiol

    (2003)
  • BersD.M.

    Altered cardiac myocyte Ca regulation in heart failure

    Physiology (Bethesda)

    (2006)
  • BersD.M. et al.

    Calcium signaling in cardiac ventricular myocytes

    Ann N Y Acad Sci

    (2005)
  • BessacB.F. et al.

    TRPM7 channel is sensitive to osmotic gradients in human kidney cells

    J Physiol

    (2007)
  • BezzeridesV.J. et al.

    Rapid vesicular translocation and insertion of TRP channels

    Nat Cell Biol

    (2004)
  • BialeckiR.A. et al.

    Stretching increases calcium influx and efflux in cultured pulmonary arterial smooth muscle cells

    Am J Physiol

    (1992)
  • BourqueC.W.

    Central mechanisms of osmosensation and systemic osmoregulation

    Nat Rev Neurosci

    (2008)
  • ChenX.Z. et al.

    Submembraneous microtubule cytoskeleton: interaction of TRPP2 with the cell cytoskeleton

    Febs J

    (2008)
  • ChiangC.S. et al.

    Capping transmembrane helices of MscL with aromatic residues changes channel response to membrane stretch

    Biochemistry

    (2005)
  • ChristensenA.P. et al.

    TRP channels in mechanosensation: direct or indirect activation?

    Nat Rev Neurosci

    (2007)
  • CraeliusW.

    Stretch-activation of rat cardiac myocytes

    Exp Physiol

    (1993)
  • DalrympleA. et al.

    Mechanical stretch regulates TRPC expression and calcium entry in human myometrial smooth muscle cells

    Mol Hum Reprod

    (2007)
  • DavisP.F.

    Hemodynamic shear stress and the endothelium in cardiovascular pathophysiology

    Nat. Clin. Pract.

    (2009)
  • DavisM.J. et al.

    Signaling mechanisms underlying the vascular myogenic response

    Physiol Rev

    (1999)
  • DavisM.J. et al.

    Stretch-activated single-channel and whole cell currents in vascular smooth muscle cells

    Am J Physiol

    (1992)
  • DavisM.J. et al.

    Stretch-induced increases in intracellular calcium of isolated vascular smooth muscle cells

    Am J Physiol

    (1992)
  • DedmanA. et al.

    The mechano-gated K(2P) channel TREK-1

    Eur Biophys J

    (2008)
  • DelmasP.

    Polycystins: polymodal receptor/ion-channel cellular sensors

    Pflugers Arch

    (2005)
  • DietrichA. et al.

    Pressure-induced and store-operated cation influx in vascular smooth muscle cells is independent of TRPC1

    Pflugers Arch

    (2007)
  • DietrichA. et al.

    Increased vascular smooth muscle contractility in TRPC6−/− mice

    Mol Cell Biol

    (2005)
  • DrummondH.A. et al.

    A new trick for an old dogma: ENaC proteins as mechanotransducers in vascular smooth muscle

    Physiology (Bethesda)

    (2008)
  • FeletouM. et al.

    Endothelium-dependent hyperpolarizations: past beliefs and present facts

    Ann Med

    (2007)
  • FengN.H. et al.

    Transient receptor potential vanilloid type 1 channels act as mechanoreceptors and cause substance P release and sensory activation in rat kidneys

    Am J Physiol Renal Physiol

    (2008)
  • Cited by (0)

    View full text