Published online before print September 24, 2009, doi: 10.1161/CIRCRESAHA.109.206581
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© 2009 American Heart Association, Inc.
Integrative Physiology |
TRPC1 Channels Are Critical for Hypertrophic Signaling in the Heart
From the Department of Medicine (M.S., Z.-S.Z., L.M., V.G., J.B., J.S., M.W., H.A.R., P.R.), Duke University School of Medicine, Durham, NC; Department of Cell Biology (L.T.), University of Oklahoma Health Sciences Center, Oklahoma City; and Laboratory of Neurobiology (J.A., L.B.), National Institute of Environmental Health Sciences, Research Triangle Park, NC.
Correspondence to Paul Rosenberg, Suite 200, 4321 Medical Park Dr, Durham, NC 27704. E-mail rosen029{at}mc.duke.edu
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Abstract |
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Rationale: Cardiac muscle adapts to increase workload by altering cardiomyocyte size and function resulting in cardiac hypertrophy. G protein–coupled receptor signaling is known to govern the hypertrophic response through the regulation of ion channel activity and downstream signaling in failing cardiomyocytes.
Objective: Transient receptor potential canonical (TRPC) channels are G protein–coupled receptor operated channels previously implicated in cardiac hypertrophy. Our objective of this study is to better understand how TRPC channels influence cardiomyocyte calcium signaling.
Methods and Results: Here, we used whole cell patch clamp of adult cardiomyocytes to show upregulation of a nonselective cation current reminiscent of TRPC channels subjected to pressure overload. This TRPC current corresponds to the increased TRPC channel expression noted in hearts of mice subjected to pressure overload. Importantly, we show that mice lacking TRPC1 channels are missing this putative TRPC current. Moreover, Trpc1–/– mice fail to manifest evidence of maladaptive cardiac hypertrophy and maintain preserved cardiac function when subjected to hemodynamic stress and neurohormonal excess. In addition, we provide a mechanistic basis for the protection conferred to Trpc1–/– mice as mechanosensitive signaling through calcineurin/NFAT, mTOR and Akt is altered in Trpc1–/– mice.
Conclusions: From these studies, we suggest that TRPC1 channels are critical for the adaptation to biomechanical stress and TRPC dysregulation leads to maladaptive cardiac hypertrophy and failure.
Key Words: transient receptor potential channels • G protein receptor signaling • cardiac hypertrophy
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Introduction |
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Cardiac myocytes respond to changing mechanical workloads by altering the frequency and amplitude of their calcium transients.1,2 Encoded in these calcium transients are signals that alter not only the immediate contractile response but also initiate and maintain a remodeling response that adjusts cellular mass, ionic currents, kinetic properties of contractile proteins, and metabolic capacity.3 It is likely that persistence of these signals modulate the calcium signaling events resulting in a hypertrophic response and adverse remodeling. To identify the proximal signals that regulate cardiac hypertrophy, attention has begun to focus on ion channels because they may link mechanical activity to cell signaling.4 Recent work has raised the possibility that hypertrophic agonists linked to G-protein coupled receptors activate calcium entry through transient receptor potential canonical (TRPC) channels.5–10
TRPC channels encompass a large family of nonselective cation channels found in many different cell types.11 TRPC channels are activated downstream of G-protein receptor through the phospholipase C signaling by inositol trisphosphate (TRPC1/4/5) or by diacyl glycerol (TRPC3/6/7).5,12 More recently TRPC1/6 channels were found to be mechanosensitive channels that mediate nonselective cation entry in response to increased membrane stretch.6,7 These findings raise interesting possibilities about TRPC channels as mechanosensitive channels that may be operative during cardiomyocyte stretch associated with pressure overload. In fact, several groups have linked increased TRPC channel activity to cardiac hypertrophy and failure.8–10,13 TRPC1/C3/C6 have been found to be upregulated in response to pressure overload and a model of calcineurin-mediated cardiomyopathy. Moreover, transgenic mice overexpressing either TRPC3 or TRPC6 channels in the heart manifest an exaggerated hypertrophic response to pressure overload or die prematurely from heart failure.9,13 In contrast, a TRPC3 specific small molecule inhibitor prevented the development of cardiac hypertrophy in wild-type (WT) mice subjected to pressure overload.14 Despite some evidence suggesting a link between TRPC channels and cardiac hypertrophy, the molecular mechanism by which TRPC channels contribute to cardiac calcium signaling is not known. We therefore tested the hypothesis TRPC1 channels contribute to biomechanical signaling following pressure overload in the cardiomyocytes and we provide direct evidence that TRPC1 is a key mediator of the cardiac hypertrophic response. Our findings support a concept that therapeutic strategies designed to block TRPC1 channels may have clinical benefit in the hypertrophic failing heart.
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Methods |
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An expanded Methods section is available in the Online Data Supplement at http://circres.ahajournals.org. All animal experimental procedures were reviewed and approved by the Institutional Animal Care and Use Committees of Duke University.
In brief, Trpc1–/– and WT mice were maintained in a 129 background for more greater than seven generations. Paired mice were used in each study. Cardiac stress was induced using transverse aortic constriction (TAC) surgery or chronic angiotensin infusion. Adult cardiomyocytes were prepared using Langendorff perfusion to disaggregate single cells. Patch clamp using whole cell technique and calcium imaging with Fura-2 acetoxymethyl ester were used to measure TRPC1 currents and calcium entry. Cardiac lysates were prepared for biochemical assays of relevant signaling pathways. Cryosectioning of hearts was performed for histological studies.
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Results |
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Trpc1–/– and Cardiac Hypertrophy
We first designed studies to test the hypothesis that TRPC1 mediated calcium entry in cardiomyocytes activates hypertrophic signaling. Trpc1–/– mice and WT mice were subjected to TAC to induce cardiac hypertrophy. Histological sections of hearts from WT mice demonstrated a marked increase in left ventricle (LV) size after 8 weeks of TAC compared to sham operated mice (Figure 1A, top row). In contrast, the hearts of Trpc1–/– mice did not demonstrate significant cardiac hypertrophy (Figure 1A, top row), nor was there an increase in collagen deposition as determined by Sirius red staining compared to the heart sections of WT mice (Figure 1A, bottom row).
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Serial echocardiograms (performed at 0, 4, and 8 weeks) demonstrated a progressive decline in the percentage fractional shortening of WT mice, whereas Trpc1–/– mice maintained preserved percentage fractional shortening over a wide range of systolic pressure gradients (0 to 150 mm Hg) (Figure 1B and Online Table I). A detailed statistical analysis for fractional shortening and LV mass/body weight (BW) ratio has been shown in Online Table III and Online Figure II. Invasive LV hemodynamic parameters measured from WT and Trpc1–/– mice showed significant differences in the LV +dP/dtmax and LV –dP/dtmin only after the TAC operation. These data indicate that the loss of TRPC1 is associated with preserved contractility despite a marked increase in pressure load (Online Table I).
Consistent with the observations made by echocardiography and hemodynamics, we found marked difference in cardiac mass between hearts of Trpc1–/– mice subjected to TAC compared to WT mice. The increase in cardiac mass following TAC was significantly reduced in the Trpc1–/– mice as was evident by the change in LV mass/BW ratio (3.1±0.23 to 4.5±0.175, before and after TAC, respectively) as compared to WT mice (3.3±0.14 to 6.8±0.42) (Figure 1C and Online Table I). Thus, it is apparent from these data that Trpc1–/– mice respond to pressure overload with a modest increase in cardiac mass and preserved cardiac function, whereas the same level of pressure overload in WT mice produced significant cardiac impairment. We also considered whether changes in TRPC2–7 channel expression occurred in the hearts of the Trpc1–/– mice as mechanism for the protection seen in the INSC. In fact, TRPC channels (mRNA or protein) at baseline and after pressure overload did not differ between WT and Trpc1–/– mice (Online Figure I, A through D).
TRPC channels are known to be receptor operated cation channels activated downstream of G-protein coupled receptors, eg, angiotensin II (Ang II), raising the possibility that Ang II mediated hypertrophic signaling may influence TRPC signaling9,15–17 WT and Trpc1–/– mice infused with Ang II (1000 ng/kg per minute) for 4 weeks (28 days) to induce cardiac hypertrophy (Figure 1D and Online Table II).
INSC in Adult Cardiomyocytes
Next, we designed whole cell voltage clamp studies to measure TRPC currents from isolated adult cardiomyocytes taken from WT or Trpc1–/– mice. Solutions were configured so as to limit voltage gated Ca2+ and K+ currents mainly by including inhibitors of L-type calcium channels and Cs+ to block K+ channels. We used an inverse ramp protocol from +100 mV to –100 mV to limit voltage gated Na+ channel currents and holding potential of 0 mV (see expanded Methods section in the Online Data Supplement).18 Figure 2A displays current–time plots recorded from WT (brown traces) and Trpc1–/– (blue traces) cardiomyocytes 8 weeks after the TAC operation. WT cardiomyocytes displayed a greater current recorded at both +80 mV and –80 mV membrane potentials compared to Trpc1–/– cardiomyocytes. The nonselective currents were inhibited by gadolinium (Gd3+), a known TRPC channel blocker (Figure 2A). We noted that the current–voltage relationship recorded from sham and TAC operated mice was linear in shape with a reversal potential of 0 mV, features reminiscent of nonselective TRPC channels (Figure 2B). Interestingly nonselective currents recorded from cardiomyocytes taken from Trpc1–/– mice displayed similar current–voltage relations with zero reversal potential (Figure 2C). However, the current density of the nonselective currents recorded from Trpc1–/– cardiomyocytes, both sham and TAC operated mice, was markedly reduced compared to the WT cardiomyocytes (Figure 2D).
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To characterize the INSC recorded from cardiomyocytes, we sought evidence for the contributions of TRPC from cation selectivity, pharmacological profiling and gating mechanism (Figure 2E). Replacing Na+ in the external solution with N-methyl-D-glucamine dramatically reduced the nonselective current by greater than 50% from WT cardiomyocytes indicating the current is in part permeable to Na+. In addition, the INSC was rapidly blocked by the addition of gadolinium (Gd3+, 10 µmol/L) to the perfusion bath. Trivalent cation block of the INSC is a characteristic feature of TRPC currents.19 We also found that the putative TRPC1 current was equally permeable to calcium and barium which would further suggest this current is in part contributed by TRPC1 (Figure 2E). We found no difference in the Li3+ sensitive currents in cardiomyocytes isolated from WT and Trpc1–/– mice, indicating no change in NCX1 (Na+/Ca2+ exchange) currents (data not shown).20 In addition, we found that immunolabeled TRPC1 only partially overlapped with that of NCX1 (Online Figure I, E). When considered in total these results indicate that TRPC1 is likely to contribute to the nonselective cation background current recorded in adult cardiomyocytes.
Given the central role of the neurohormone angiotensin-II (Ang II) in the stretch activated signaling in the cardiomyocyte,21 we tested whether Ang II application influenced the nonselective cation current attributed to TRPC1. Ang II stimulation of WT cardiomyocytes resulted in two-fold increase in the current density of the nonselective current (Figure 2F). In contrast, Ang II failed to augment the TRPC current in cardiomyocytes isolated from Trpc1–/– mice (Figure 2F). We also tested whether TRPC1 currents were activated by 1-oleoyl-2-acetyl-sn-glycerol (OAG), a stable cell permeable analog of DAG (Figure 2G). Here, perfusion of cardiomyocytes with OAG (10 µmol/L) activated a nonselective current similar to that seen with Ang II. We found that the current density of OAG activated currents from Trpc1–/– and WT cardiomyocytes were not different (Figure 2G). These results indicate that TRPC1 contributes to the Ang II–induced nonselective current, whereas TRPC1 does not influence the DAG-induced current. TRPC1 has also been implicated in store operated calcium entry as a SOC channel in many cell types including cardiomyocytes. However, we did not find a difference in the rate of Ca2+ entry following store depletion in Trpc1–/– neonatal cardiomyocytes compared to WT cells (Online Figure III). These findings support our model in which TRPC1 channels respond to G protein signaling that is involved in the pressure overload response.
TRPC1 and the Stretch Response
We next determined whether cardiomyocytes from Trpc1–/– mice responded differently to mechanical stretch than WT cardiomyocytes. Isolated neonatal cardiomyocytes subjected to a cyclic stretch at 15% strain at 1-Hz frequency for 8 to 24 hours duration expressed augmented levels of brain natriuretic factor (BNP) and atrial natriuretic factor (ANF) in a time-dependent manner (Figure 3A) peaking at 24 hours with a 7 fold increase in the BNP and ANF expression. Interestingly, treating WT cells with losartan to block angiotensin type 1 receptors (AT1Rs) prevented the induction of the stretch gene program. Moreover, Trpc1–/– cardiomyocytes showed no change in the expression of BNP and ANF over any time point examined. Thus, neonatal cardiomyocytes lacking TRPC1 displayed a blunted response to stretch in comparison to WT cardiomyocytes. The blocking of stretch response by losartan treatment suggests that TRPC1 mediated stretch signaling is downstream of the AT1R.
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It has been recently shown that mechanical stretch activates AT1R in an agonist independent manner that can result in activation of a nonselective cation current in vascular smooth muscle cells.22 These results may explain the recent findings demonstrating TRPC1 and TRPC6 channels as putative stretch activated channels.7 We, therefore, tested whether stretch influences the TRPC1 current in adult cardiomyocytes. Here, osmotic stress applied to the cardiomyocytes, by changing the osmolarity of the perfusion bath from 305 to 205 mOsm, increased the nonselective current (Iswell) in WT cardiomyocytes. The current–voltage relationship of the Iswell from adult cardiomyocytes strongly resembled that observed above for pressure overload and Ang II. Osmotic stress did not activate the nonselective current in cardiomyocytes lacking TRPC1 (Figure 3B and 3C). We further characterized the Iswell in WT cardiomyocytes to determine whether Ang II signaling was involved in the osmotic activated currents. Inclusion of the phospholipase C blocker U-73122 in the pipette solution decreased the nonselective current at baseline and following cell swelling induced by osmotic stress (Figure 3D and 3F). We also demonstrate that the Iswell in WT cardiomyocytes signals through the Ang II receptor as the current was significantly blocked by losartan (10 µmol/L) compared to vehicle treated WT cardiomyocytes (Figure 3E and 3F). These data indicate Ang II signaling is fundamental to the current activated by cell swelling. Moreover, WT cardiomyocytes treated with tarantula toxin GsMTx-4, an inhibitor of stretch-activated channels also blocked the nonselective current induced by cell swelling, providing additional evidence that TRPC1 acts as a stretch activated channel (data not shown).6,23 Collectively, these studies show that Trpc1–/– cardiomyocytes, in comparison to WT cells, fail to respond to different forms of stretch as indicated by the lack of stretch activated nonselective cation current (swelling and positive pressure) or changes in ANF and BNP mRNA expression (radial stretch). These results provide evidence in support of our model in which TRPC1 channels reside downstream of stretch-activated G protein–coupled receptor (GPCR) signaling to confer stretch dependent signaling associated with cardiac hypertrophy.
Loss of TRPC1 Alters Hypertrophic Signaling
To this point, our studies indicated that mice lacking TRPC1 are protected from the deleterious effects of pressure overload. Because it is now well established that calcium entry through TRPC channels influences calcineurin/NFAT (nuclear factor of activated T cells) signaling in many cell types including cardiomyocytes, we examined the phosphorylation state of NFATC3 in cardiac lysates prepared from WT and Trpc1–/– mice as a marker of calcineurin/NFAT signaling. NFATC3 is dephosphorylated by calcineurin in pressure-overloaded hearts as was detected in the WT mice in Figure 4A. We then examined whether the loss of TRPC1 influenced NFAT signaling. First, we found a significant increase in phospho-NFATC3 in the heart lysates prepared from sham operated Trpc1–/– mice compared to WT mice indicating that more NFATC3 exists in the inactive state in the sham operated Trpc1–/– mice (Figure 4A). No differences in total NFAT were seen among WT and Trpc1–/– mice, but a greater fraction of NFATC3 existed in the phosphorylated state in TAC operated Trpc1–/– mice compared to TAC operated WT mice (Figure 4A). These data suggest that calcineurin/NFAT activity in the hearts of mice lacking TRPC1 is less active at baseline and after pressure overload (Figure 4B).
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We next designed studies using a transgenic NFAT indicator mice24,25 to further examine the relationship between TRPC1 and calcineurin/NFAT signaling. Neonatal cardiomyocytes from NFAT indicator mice were infected with adenoviruses carrying either TRPC1 small interfering RNA (siTRPC1) or control small interfering RNA (scrambled) constructs (Figure 4C). Cardiomyocytes were stimulated with Ang II to alter the frequency of spontaneous calcium oscillations and activate the hypertrophic program (Figure 4D). In cells with TRPC1 silencing, we found a marked attenuation of the calcium oscillations compared to control silenced cells (Figure 4D through 4F). This change in the oscillation frequency in the siTRPC1 neonatal cardiomyocytes corresponded to a reduction in NFAT transactivation, as measured by LacZ reporter gene compared to control neonatal cardiomyocytes. These results support our in vivo studies suggesting that TRPC1 channels provide calcium entry needed for hypertrophic signaling through the calcineurin/NFAT signaling pathway in cardiomyocytes (Figure 4G).
TRPC1 and Hypertrophic Gene Expression
Cardiac hypertrophy with diminished cardiac function has long been associated with changes in profiles of gene expression.26 We, therefore, measured the mRNA for BNP and ANF from the hearts of Trpc1–/– and WT mice (sham- and TAC-operated). These neurohormones are released by cardiomyocytes subjected to increased wall stress and are important biomarkers for the activation of the fetal gene program in response to cardiac stress.27 WT mice subjected to pressure overload were found to have a nine fold increase in the expression of BNP and 16-fold increase in ANF; whereas Trpc1–/– mice subjected to TAC showed no significant change in BNP and ANF expression (Figure 5A). We also found that the expression of the calcium pump, sarcoplasmic/endoplasmic calcium ATPase (SERCA)2a, was decreased in the TAC-WT mice, whereas there was no corresponding reduction in SERCA2a expression in Trpc1–/– mice subjected to TAC. SERCA2a is known to be diminished in heart failure and may contribute to abnormal calcium signaling.28 It is clear from these studies that the attenuated cardiac hypertrophy and preserved cardiac function observed in mice lacking TRPC1 accompanied no changes in the gene expression profile associated with maladaptive cardiac hypertrophy.
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To better understand the survival advantage offered to Trpc1–/– mice in response to pressure overload, we next tested the hypothesis that Akt signaling pathways associated with cardiomyocyte survival would be enhanced in the Trpc1–/– mice. In fact, we were unable to discern differences in the level of phospho-Akt between the sham and TAC operation in WT mice. In contrast, Akt phosphorylation was notably increased in heart lysates prepared from Trpc1–/– mice following the TAC operation. Likewise, phospho-mTOR (mammalian target of rapamycin) was markedly increased in the heart lysates of Trpc1–/– TAC operated mice compared to WT mice. No differences were noted in the total Akt or mTOR expression of WT or Trpc1–/– hearts (Figure 5B and 5C). These results suggest that the preserved cardiac function and minimal changes to cardiac mass following pressure overload seen in mice lacking TRPC1 may be due in part to the preserved Akt and mTOR signaling which are associated with cell survival.
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Discussion |
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In the present work, we reveal a highly specific role for TRPC1 as a nonselective cation channel in cardiomyocytes that participates in cardiac hypertrophic signaling. In particular, we show that mice lacking TRPC1 are protected from the deleterious effects of increased intracardiac pressures imposed by various forms of cardiac stress (pressure overload or chronic Ang II stimulation). These findings provide the strongest support to date that TRPC channels play a significant role in the pathophysiology of cardiac hypertrophy.
Recent reports have suggested that TRPC1 and TRPC6 are stretch activated cation channels.7,22 How the TRPC channels sense changes in stretch and what molecular mechanism leads to TRPC1 channel gating is presently unknown. It has been proposed that TRPC channels either respond directly to deformation of the lipids in plasma membranes or as a downstream consequence of AT1R activation.22,29 We have recently suggested that the scaffolding protein homer-1 links TRPC1 with the cytoskeleton in skeletal muscle.30 In the present study, cardiomyocytes lacking TRPC1 are protected from pressure overload which further supports our model. Under normal hemodynamic conditions TRPC1 plays a role in adjusting cytoskeletal stiffness associated with loading conditions. However, under pathological workloads TRPC1 currents are augmented in response to more TRPC1 channel expression resulting in the activation of adverse remodeling associated with cardiac hypertrophy. It will be important to know in future studies whether TRPC channels connected to the homer-cytoskeleton are influenced by GPCR activation as has been suggested for TRPC1, homer and mGluR receptors in neurons.31,32
TRPC channels are nonselective cation channels and cation flux through TRPC channels have been implicated in other mammalian physiological processes including learning and memory in the brain and glomerular slit diaphragm function in kidney epithelial cells.33,34 The present work, along with other recent reports, establishes that TRPC channels are located at the sarcolemma where TRPC1 mediated cation flux influences the transition from adaptive to maladaptive cardiac hypertrophy. What is the common link between TRPC channel activity in neurons, podocytes and cardiomyocytes? In neurons TRPC channels are important modulators of the cytoskeleton where growth cones turn and extend processes in response to local growth factor concentrations.34–38 In the podocyte, activating mutations in TRPC6 disrupt the normal function of the foot process which is highly dependent on the integrity of the actin cytoskeleton and GPCR signaling.39,40 According to our model, TRPC channels act downstream of GPCR signaling that influences membrane–cytoskeletal interactions to accommodate specific cellular signaling events. Under conditions of pressure overload, TRPC1 calcium entry is likely to influence hypertrophic signaling resulting in the remodeling response that leads to heart failure. Future efforts to block these channels may offer novel strategies to treat cardiac hypertrophy and failure.
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Acknowledgments |
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We thank Dr Sanjeev Ahuja and Dr Cary Ward.
Sources of Funding
This work was supported by NIH grant R01-HL093470 (to P.R.), the Mandel Center at Duke (P.R.), and a Muscular Dystrophy Association research award (P.R.) and, in part, by the Intramural Program of the NIH, National Institute of Environmental Health Sciences (to J.A. and L.B.).
Disclosures
None.
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Footnotes |
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Original received November 6, 2008; resubmission received August 5, 2009; revised resubmission received September 7, 2009; accepted September 15, 2009.
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References |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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1. Hill JA, Olson EN. Cardiac plasticity. N Engl J Med. 2008; 358: 1370–1380.
2. Williams RS, Rosenberg P. Calcium-dependent gene regulation in myocyte hypertrophy and remodeling. Cold Spring Harb Symp Quant Biol. 2002; 67: 339–344.
3. Berridge MJ. Microdomains and elemental events in calcium signalling. Cell Calcium. 1996; 20: 95–96.[CrossRef][Medline] [Order article via Infotrieve]
4. McKinsey TA, Kass DA. Small-molecule therapies for cardiac hypertrophy: moving beneath the cell surface. Nat Rev Drug Discov. 2007; 6: 617–635.[CrossRef][Medline] [Order article via Infotrieve]
5. Hofmann T, Obukhov AG, Schaefer M, Harteneck C, Gudermann T, Schultz G. Direct activation of human TRPC6 and TRPC3 channels by diacylglycerol. Nature. 1999; 397: 259–263.[CrossRef][Medline] [Order article via Infotrieve]
6. Spassova MA, Hewavitharana T, Xu W, Soboloff J, Gill DL. A common mechanism underlies stretch activation and receptor activation of TRPC6 channels. Proc Natl Acad Sci U S A. 2006; 103: 16586–16591.
7. Maroto R, Raso A, Wood TG, Kurosky A, Martinac B, Hamill OP. TRPC1 forms the stretch-activated cation channel in vertebrate cells. Nat Cell Biol. 2005; 7: 179–185.[CrossRef][Medline] [Order article via Infotrieve]
8. Seth M, Sumbilla C, Mullen SP, Lewis D, Klein MG, Hussain A, Soboloff J, Gill DL, Inesi G. Sarco(endo)plasmic reticulum Ca2+ ATPase (SERCA) gene silencing and remodeling of the Ca2+ signaling mechanism in cardiac myocytes. Proc Natl Acad Sci U S A. 2004; 101: 16683–16688.
9. Kuwahara K, Wang Y, McAnally J, Richardson JA, Bassel-Duby R, Hill JA, Olson EN. TRPC6 fulfills a calcineurin signaling circuit during pathologic cardiac remodeling. J Clin Invest. 2006; 116: 3114–3126.[CrossRef][Medline] [Order article via Infotrieve]
10. Onohara N, Nishida M, Inoue R, Kobayashi H, Sumimoto H, Sato Y, Mori Y, Nagao T, Kurose H. TRPC3 and TRPC6 are essential for angiotensin II-induced cardiac hypertrophy. EMBO J. 2006; 25: 5305–5316.[CrossRef][Medline] [Order article via Infotrieve]
11. Clapham DE, Runnels LW, Strubing C. The TRP ion channel family. Nat Rev Neurosci. 2001; 2: 387–396.[Medline] [Order article via Infotrieve]
12. Zhu X, Chu PB, Peyton M, Birnbaumer L. Molecular cloning of a widely expressed human homologue for the Drosophila trp gene. FEBS Lett. 1995; 373: 193–198.[CrossRef][Medline] [Order article via Infotrieve]
13. Nakayama H, Wilkin BJ, Bodi I, Molkentin JD. Calcineurin-dependent cardiomyopathy is activated by TRPC in the adult mouse heart. FASEB J. 2006; 20: 1660–1670.
14. Kiyonaka S, Kato K, Nishida M, Mio K, Numaga T, Sawaguchi Y, Yoshida T, Wakamori M, Mori E, Numata T, Ishii M, Takemoto H, Ojida A, Watanabe K, Uemura A, Kurose H, Morii T, Kobayashi T, Sato Y, Sato C, Hamachi I, Mori Y. Selective and direct inhibition of TRPC3 channels underlies biological activities of a pyrazole compound. Proc Natl Acad Sci U S A. 2009; 106: 5400–5405.
15. Dietrich A, Mederos Y, Schnitzler M, Gollasch M, Gross V, Storch U, Dubrovska G, Obst M, Yildirim E, Salanova B, Kalwa H, Essin K, Pinkenburg O, Luft FC, Gudermann T, Birnbaumer L. Increased vascular smooth muscle contractility in TRPC6-/- mice. Mol Cell Biol. 2005; 25: 6980–6989.
16. Ohba T, Watanabe H, Murakami M, Takahashi Y, Iino K, Kuromitsu S, Mori Y, Ono K, Iijima T, Ito H. Upregulation of TRPC1 in the development of cardiac hypertrophy. J Mol Cell Cardiol. 2007; 42: 498–507.[CrossRef][Medline] [Order article via Infotrieve]
17. Bush EW, Hood DB, Papst PJ, Chapo JA, Minobe W, Bristow MR, Olson EN, McKinsey TA. Canonical transient receptor potential channels promote cardiomyocyte hypertrophy through activation of calcineurin signaling. J Biol Chem. 2006; 281: 33487–33496.
18. Fauconnier J, Lanner JT, Sultan A, Zhang SJ, Katz A, Bruton JD, Westerblad H. Insulin potentiates TRPC3-mediated cation currents in normal but not in insulin-resistant mouse cardiomyocytes. Cardiovasc Res. 2007; 73: 376–385.
19. Clapham DE. Sorting out MIC, TRP, and CRAC ion channels. J Gen Physiol. 2002; 120: 217–220.
20. Eder P, Probst D, Rosker C, Poteser M, Wolinski H, Kohlwein SD, Romanin C, Groschner K. Phospholipase C-dependent control of cardiac calcium homeostasis involves a TRPC3-NCX1 signaling complex. Cardiovasc Res. 2007; 73: 111–119.
21. Sadoshima J, Xu Y, Slayter HS, Izumo S. Autocrine release of angiotensin II mediates stretch-induced hypertrophy of cardiac myocytes in vitro. Cell. 1993; 75: 977–984.[CrossRef][Medline] [Order article via Infotrieve]
22. Mederos y Schnitzler M, Storch U, Meibers S, Nurwakagari P, Breit A, Essin K, Gollasch M, Gudermann T. Gq-coupled receptors as mechanosensors mediating myogenic vasoconstriction. EMBO J. 2008; 27: 3092–3103.[CrossRef][Medline] [Order article via Infotrieve]
23. Stiber JA, Zhang ZS, Burch J, Eu JP, Zhang S, Truskey GA, Seth M, Yamaguchi N, Meissner G, Shah R, Worley PF, Williams RS, Rosenberg PB. Mice lacking Homer 1 exhibit a skeletal myopathy characterized by abnormal transient receptor potential channel activity. Mol Cell Biol. 2008; 28: 2637–2647.
24. Konhilas JP, Watson PA, Maass A, Boucek DM, Horn T, Stauffer BL, Luckey SW, Rosenberg P, Leinwand LA. Exercise can prevent and reverse the severity of hypertrophic cardiomyopathy. Circ Res. 2006; 98: 540–548.
25. Rosenberg P, Hawkins A, Stiber J, Shelton JM, Hutcheson K, Bassel-Duby R, Shin DM, Yan Z, Williams RS. TRPC3 channels confer cellular memory of recent neuromuscular activity. Proc Natl Acad Sci U S A. 2004; 101: 9387–9392.
26. Perrino C, Naga Prasad SV, Mao L, Noma T, Yan Z, Kim HS, Smithies O, Rockman HA. Intermittent pressure overload triggers hypertrophy-independent cardiac dysfunction and vascular rarefaction. J Clin Invest. 2006; 116: 1547–1560.[CrossRef][Medline] [Order article via Infotrieve]
27. Brenner JS, Dolmetsch RE. TrpC3 regulates hypertrophy-associated gene expression without affecting myocyte beating or cell size. PLoS ONE. 2007; 2: e802.[CrossRef][Medline] [Order article via Infotrieve]
28. He H, Giordano FJ, Hilal-Dandan R, Choi DJ, Rockman HA, McDonough PM, Bluhm WF, Meyer M, Sayen MR, Swanson E, Dillmann WH. Overexpression of the rat sarcoplasmic reticulum Ca2+ ATPase gene in the heart of transgenic mice accelerates calcium transients and cardiac relaxation. J Clin Invest. 1997; 100: 380–389.[Medline] [Order article via Infotrieve]
29. Gottlieb P, Folgering J, Maroto R, Raso A, Wood TG, Kurosky A, Bowman C, Bichet D, Patel A, Sachs F, Martinac B, Hamill OP, Honoré E. Revisiting TRPC1 and TRPC6 mechanosensitivity. Pflugers Arch. 2008; 455: 1097–1103.[CrossRef][Medline] [Order article via Infotrieve]
30. Usui S, Konno D, Hori K, Maruoka H, Okabe S, Fujikado T, Tano Y, Sobue K. Synaptic targeting of PSD-Zip45 (homer 1c) and its involvement in the synaptic accumulation of F-actin. J Biol Chem. 2003; 278: 10619–10628.
31. Ango F, Prezeau L, Muller T, Tu JC, Xiao B, Worley PF, Pin JP, Bockaert J, Fagni L. Agonist-independent activation of metabotropic glutamate receptors by the intracellular protein Homer. Nature. 2001; 411: 962–965.[CrossRef][Medline] [Order article via Infotrieve]
32. Tu JC, Xiao B, Yuan JP, Lanahan AA, Leoffert K, Li M, Linden DJ, Worley PF. Homer binds a novel proline-rich motif and links group 1 metabotropic glutamate receptors with IP3 receptors. Neuron. 1998; 21: 717–726.[CrossRef][Medline] [Order article via Infotrieve]
33. Winn MP, Conlon PJ, Lynn KL, Farrington MK, Creazzo T, Hawkins AF, Daskalakis N, Kwan SY, Ebersviller S, Burchette JL, Pericak-Vance MA, Howell DN, Vance JM, Rosenberg PB. A mutation in the TRPC6 channel causes familial focal segmental glomerulosclerosis. Science. 2005; 308: 1801–1804.
34. Strubing C, Krapivinsky G, Krapivinsky L, Clapham DE. TRPC1 and TRPC5 form a novel cation channel in mammalian brain. Neuron. 2001; 29: 645–655.[CrossRef][Medline] [Order article via Infotrieve]
35. Wen Z, Han L, Bamburg JR, Shim S, Ming GL, Zheng JQ. BMP gradients steer nerve growth cones by a balancing act of LIM kinase and Slingshot phosphatase on ADF/cofilin. J Cell Biol. 2007; 178: 107–119.
36. Shim S, Goh EL, Ge S, Sailor K, Yuan JP, Roderick HL, Bootman MD, Worley PF, Song H, Ming GL. XTRPC1-dependent chemotropic guidance of neuronal growth cones. Nat Neurosci. 2005; 8: 730–735.[CrossRef][Medline] [Order article via Infotrieve]
37. Bezzerides VJ, Ramsey IS, Kotecha S, Greka A, Clapham DE. Rapid vesicular translocation and insertion of TRP channels. Nat Cell Biol. 2004; 6: 709–720.[CrossRef][Medline] [Order article via Infotrieve]
38. Greka A, Navarro B, Oancea E, Duggan A, Clapham DE. TRPC5 is a regulator of hippocampal neurite length and growth cone morphology. Nat Neurosci. 2003; 6: 837–845.[CrossRef][Medline] [Order article via Infotrieve]
39. Faul C, Asanuma K, Yanagida-Asanuma E, Kim K, Mundel P. Actin up: regulation of podocyte structure and function by components of the actin cytoskeleton. Trends Cell Biol. 2007; 17: 428–437.[CrossRef][Medline] [Order article via Infotrieve]
40. Möller CC, Wei C, Altintas MM, Li J, Greka A, Ohse T, Pippin JW, Rastaldi MP, Wawersik S, Schiavi S, Henger A, Kretzler M, Shankland SJ, Reiser J. Induction of TRPC6 channel in acquired forms of proteinuric kidney disease. J Am Soc Nephrol. 2007; 18: 29–36.
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