Associate editor: M. EndohMechanosensitive TRP channels in cardiovascular pathophysiology
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.
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