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Liedtke WB, Heller S, editors. TRP Ion Channel Function in Sensory Transduction and Cellular Signaling Cascades. Boca Raton (FL): CRC Press/Taylor & Francis; 2007.

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TRP Ion Channel Function in Sensory Transduction and Cellular Signaling Cascades.

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Chapter 28A New Insight into the Function of TRPV2 in Circulatory Organs

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The TRPV subfamily has had increasing attention since some channels in this group have been shown to be sensitive to a broad range of environmental stimuli, including heat, osmosensitivity, and mechanical stress. In addition, TRPV proteins are widely expressed in a range of cell types in lower and higher organisms. Although some TRPVs were originally found in the sensory system, ubiquitous expression in the whole body suggests that they play important roles in both sensory and nonsensory transduction functions. All mammalian homologues of TRPVs are calcium-permeable channels, with TRPV1–4 characterized as moderately calcium-selective cationic channels (Nilius, Voets et al. 2005; O'Neil and Brown 2003; Benham, Davis et al. 2002). This calcium permeability is physiologically important because Ca2+ has an obligatory role in regulating diverse cellular functions (e.g., fertilization, muscle contraction, exocytosis, and so on). There is increasing evidence that TRPV1–4 are sensitive to physical stimuli such as osmolarity, stretching, and shear stress (Liedtke and Kim 2005; O'Neil and Heller 2005). Whereas TRPV4 appears to be crucial for some relevant forms of cellular mechanosensitivity, the activation of TRPVs by mechanostress has not been fully elucidated for all channels of this group (O'Neil and Heller 2005).

Cellular responses to stretch or shear stimuli by blood flow are one of the key elements in muscle tone regulation (Figure 28.1A). In cell-attached and inside-out patch-recording modes, membrane stretch applied through the recording pipette activates nonselective cationic channels in vascular smooth muscles (Kirber et al. 1988; Davis et al. 1992; Ohya et al. 1998; see review: Beech et al. 2004). The unitary conductances range from 8 to 64 pS for monovalent cations, and a cationic channel blocker, Gd3+, is effective to block the channel. In whole-cell recordings, application of longitudinal cell stretch or cell swelling by pressure on the patch pipette or hypotonic bath solution also evokes Ca2+-permeable cationic currents in vascular myocytes (Davis et al. 1992). Additionally, in cardiac atrial and ventricular myocytes, nonselective cationic channels are activated by cell swelling as well as membrane stretch (Clemo and Baumgarten 1997; Zhang et al. 2000; Kamkin et al. 2003). Similar nonselective cationic channels sensitive to mechanical stimuli including shear stress are also identified in vascular endothelial cells (Lansman et al. 1987; Oike et al. 1994; see review: Nilius and Droogmans 2001). Although extensive studies to identify a molecular candidate of these mechanosensitive channels have been performed, information is still limited (Kanzaki, Nagasawa et al. 1999; Gillespie and Walker 2001). Nevertheless, the mechanosensitive nature of the channels seems to be conserved in higher organisms for some TRP channels, and it is likely that TRPC1, TRPC6, TRPV2, TRPM4, TRPA1, TRPP1, and possibly TRPV4 are potential candidates for the mechanosensitive channels in various native organs (Maroto et al. 2005; Welsh et al. 2002; Muraki et al. 2003; Iwata et al. 2003; Earley, Waldron et al. 2004; Corey et al. 2004; Nauli et al. 2003; Liedtke 2005). In this section, we focus on expression, function, and mechanosensitivity of TRPV2 (a member of the vanilloid receptor TRP subfamily) in circulatory organs such as vascular smooth muscles, cardiac muscles, and the endothelium. Heat activation and trafficking mechanisms of TRPV2 and expression of TRPV2 in neuronal organs will be discussed in another section (Caterina et al. 1999; Kanzaki, Zhang et al. 1999; Boels et al. 2001; Barnhill et al. 2004; Benham, Gunthorpe et al. 2003).

FIGURE 28.1. (A) Schematic diagram showing mechanical stimuli to which vascular and cardiac walls are exposed.


(A) Schematic diagram showing mechanical stimuli to which vascular and cardiac walls are exposed. (B) Potential converging pathways involved in activation of TRPV2 by mechanical stimuli: (a) involvement of ankyrin repeats in mechanoactivation of TRPV2; (more...)

Expression of TRPV2 in Circulatory Organs

TRPV2 is mainly expressed in a subpopulation of medium to large sensory neurons and is also distributed in the brain and spinal cord (Caterina et al. 1999; Bender et al. 2005). In nonsensory organs including vascular and cardiac myocytes, TRPV2 is distributed as mRNA and protein (Kanzaki, Zhang et al. 1999; Muraki et al. 2003; (Iwata et al. 2003; review: O'Neil and Brown 2003). The mRNA expression of TRPV2 is also detected in human pulmonary (Fantozzi et al. 2003) and umbilical vein endothelial cells (Figure 28.2E). Based on mRNA expression of TRPV2 in mice, it is speculated that TRPV2 is widely expressed in arterial myocytes, which can be influenced by a broad range of blood pressures (Muraki et al. 2003). Although intracellular localization of the protein was evident, some growth factors localized TRPV2 to the plasma membrane (Kanzaki, Zhang et al. 1999; Boels et al. 2001; Iwata et al. 2003). The translocation of TRPV2 was also observed when myotubes were subjected to a cyclic stretch (Iwata et al. 2003). The mechanisms of this translocation of TRPV2 are not, however, clear because PI3 kinase inhibitors are effective in some cells and not in others. Nevertheless, localization of the TRPV2 protein to the plasma membrane without treatment with growth factors is found in rat adult dorsal root ganglions, cerebral cortex (Liapi and Wood 2005), and mouse arterial myocytes (Muraki et al. 2003). Glycosylation of TRPV2 has been suggested (~95 KDa) (Kanzaki, Zhang et al. 1999), but the apparent molecular mass of TRPV2 in cardiac and aortic smooth muscles is 85–90 KDa (Iwata et al. 2003; Muraki and Imaizumi, unpublished), close to the predicted mass of full-length TRPV2 (~86 KDa).

FIGURE 28.2. Activation of human TRPV2-like channel currents in human umbilical vein endothelial cells (HUVEC).


Activation of human TRPV2-like channel currents in human umbilical vein endothelial cells (HUVEC). Activation of the channel was monitored as an increase in Ca2+ fluorescence signal in the cell. (A) In the perfusion of a bathing solution with Ca2+ (a (more...)

Mechanosensation of TRPV2 in Circulatory Organs

In vascular smooth muscles and cardiac myocytes, striking new evidence has emerged for TRPV2’s role (Muraki et al. 2003; Iwata et al. 2003) In mouse aortic mycoytes, cell swelling caused by hypotonic solution activated a nonselective cationic channel current (NSCC) and elevated [Ca2+]i. These responses were not affected by diltiazem, a Ca2+ antagonist, and caffeine, a Ca2+ releaser from the sarcoplasmic reticulum, whereas responses were effectively inhibited by ruthenium red, a TRPV blocker. Elevation of [Ca2+]i by the hypotonic stimulation but not activation of NSCC was abolished by the removal of external Ca2+, suggesting that Ca2+ entry through NSCC has an obligatory role in elevation of [Ca2+]i. Although TRPV2 and TRPV4, but not TRPV3, were present in mouse aortas as mRNA, 4αPDD, a potent activator of TRPV4, was not effective to aortic myocytes. Significant immunoreactivity to mouse TRPV2 protein was detected in mouse aortic, mesenteric, and basilar arterial myocytes. Treatment of mouse aortas with TRPV2 antisense oligonucleotides suppressed hypotonic stimulation–induced activation of NSCC and elevation of [Ca2+]i as well as expression of TRPV2 protein. Although further evidence should be gathered, these results suggest that TRPV2 in vascular myocytes is an essential component of NSCC activated by membrane stretch and cell swelling.

On the other hand, it was evident that TRPV2 expression was increased in cultured myotubes prepared from δ-sarcoglycan-deficient BIO14.6 hamster and mdx mice (a mouse model of dystrophin-deficient Duchenne muscular dystrophy). Moreover, a cyclic stretch as well as growth factors translocated TRPV2 to the plasma membrane. In BIO14.6 myotubes, 45Ca2+ uptake was greater compared with the controls and significantly inhibited by RuR. Myocyte damage measured by releasing creatine phosphokinase (CK) from myotube cytoplasm was increased in BIO14.6 myotubes to which a cyclic cell stretch was applied. In the presence of RuR, stretch-induced myocyte damage was significantly suppressed. Treatment of BIO14.6 myotubes with TRPV2 antisense oligonucleotides reduced the TRPV2 protein expression and elevation of [Ca2+]i and CK release by cyclic cell stretch, strongly indicating that TRPV2 has an obligatory role in cell abnormalities. In transgenic mice overexpressing TRPV2 in cardiac myocytes, prominent anasarca was observed at the age of ~180 days. Furthermore, the mice that died peripartum developed globally enlarged hearts. The morphological changes in the transgenic mice were similar to those observed in damaged cardiac muscles with Ca2+ overload. These results demonstrate a close link between TRPV2 expression levels and myocyte damage/loss of in vivo heart function.

In Chinese hamster ovary K1 (CHO-K1) cells transfected with mouse TRPV2 (mTRPV2-CHO), membrane stretch through the recording pipette and cell swelling caused by hypotonic solution activated NSCC, while not in control of CHO-K1. Moreover, stretch of mTRPV2–CHO cultured on an elastic silicone membrane elevated their [Ca2+]i (Muraki et al. 2003). Consistently, 45Ca2+ uptake in mTRPV2–CHO was significantly greater than in nontransfected cells, and the uptake was further enhanced by cyclic stretch (Iwata et al. 2003). Taken together, these results provide us with new insight that TRPV2 is a mechanosensitive channel.

TRPV4 also appears to display mechnosensitive properties, at least to hypotonic stress and possibly to fluid flow or shear stress. Because TRPV4 has been highly expressed in mouse aortic endothelial cells, TRPV4 is a potential candidate as a mechanosensor to shear stress/fluid flow in vascular endothelial cells (Watanabe, Vriens et al. 2002; Vriens, Watanabe et al. 2004). However, it has been reported that TRPV2 is distributed in vascular endothelial cells (Fantozzi et al. 2003; see also Figure 28.2E), suggesting that TRPV2 also has a functional role in sensing mechanical stimuli in the endothelium. As shown in Figure 28.2A, application of 70 percent hypotonic solution to HUVECS elevated [Ca2+]i in 2.2 mM Ca2+-containing bathing solution, but not in the solution without Ca2+. Hypoosmotic solution–induced elevation of [Ca2+]i was effectively inhibited by 1 and 3 μM RuR, strongly suggesting that TRPV-like channels are involved in the response. Exposure of HUVECs to 4αPDD, a TRPV4 activator, in a concentration range between 0.1 and 3 μM caused a slight increase in [Ca2+]i. In response to a mild heat stimulus (20–46°C) HUVECS exhibited a modest rise in [Ca2+]i (0.13 ± 0.01, n = 21, Figure 28.2D, open squares). In contrast, a higher heat stimulus (20–60°C, Figure 28.2D, closed circles) caused a significantly larger rise once the temperature exceeded ~55°C. Although further extensive studies are required, TRPV2 as well as TRPV4, both of which are expressed in the vascular endothelium, are potential mechanosensors in the vascular endothelium.

Potential Activation Mechanisms of TRPV2 by Mechanical Stimuli

Our studies and other additional data strongly suggest that TRPV2 may be a mechanosensor in circulatory organs. However, the mechanisms involved in opening TRPV2 by membrane stretch or hypoosmotic cell swelling have not been determined. Moreover, at present, the mechanisms in opening TRPV4 by mechanostress are not elucidated. Deletion of ankyrin repeats, which are present in the N-terminal region of TRPVs, abolished heat activation of TRPV4 (Watanabe, Vriens et al. 2002). Because the ankyrin repeats interact with certain cytoskeletal proteins, this region of TRPV2 might also be important for acceptance of applied mechanical stimuli (Figure 28.1B[a]). In addition, it is possible that cell swelling or membrane stretch produces a certain endogenous ligand that activates TRPV2 (Figure 28.1B[b]). Some fatty acids released by cell stretching modify channel activity. Metabolites of arachidonic acid or diacylglycerol might affect TRPV2 as they do TRPV4 and TRPC6 (Watanabe, Vriens et al. 2003; Slish et al. 2002). A micro-domain composed with channels, lipids, receptors, and/or enzymes could also be an effector of local change of membrane tension by membrane stretch, cell swelling, or shear stress (Figure 28.1B[c]). It has been proposed that adhesion molecules and integrins play important roles in endothelial mechanosensing in addition to their involvement in cell attachment and migration (Shyy and Chien 2002). Also TRPV4 has a tight interaction with ryanodine receptors as well as K+ channels, all of which are involved in regulating vascular tones (Earley, Heppner et al. 2005). Further studies may provide a new line of evidence of a tight interaction of TRPV2 with adhesion molecules, cytoskeletal proteins, or signal transduction units. This is important when compared with the delay of opening of the transduction channels after mechanical stimuli in fly mechanoreceptors (submillisecond response time of mechanogated channels in the fly; Earley, Heppner et al. 2005; review: Gillespie and Walker 2001): those of TRPV2 and TRPV4 after physical stimuli seem to be relatively slow (not determined precisely, at least ~1 second), indicating that these channels are mechanosensitive but not mechanogating (Figure 28.1B[d]).


TRPVs including TRPV2 display multimodal activation by diverse chemical and physical stimuli and function as molecular integrators. The available evidence demonstrates that TRPV2 appears to function as a molecular sensor of heat and mechanical stimuli. In circulatory organs, TRPV2 may regulate blood pressure and cell degeneration under some pathophysiological conditions. Other roles of TRPV2 continue to be explored in an attempt to define the role of translocation of TRPV2 by growth factors. Furthermore, mechanisms of activation of TRPV2 by mechanical stimuli and interactions of TRPV2 with functional molecules should be defined in the future.


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