TRPC1 Channels Are Critical for Hypertrophic Signaling in the Heart

Department of Medicine, Duke University School of Medicine, Durham, NC, USA.
Circulation Research (Impact Factor: 11.02). 09/2009; 105(10):1023-30. DOI: 10.1161/CIRCRESAHA.109.206581
Source: PubMed


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.
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.
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.
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.

Download full-text


Available from: Lan Mao, Oct 04, 2015
27 Reads
  • Source
    • "Well-characterized cascades and pathways regulating these homeostatic mechanisms comprise phosphoinositide 3 kinase (PI3K)/AKT, mTOR complex 1 (mTORC1), ERK1/2 and AMP-activated protein kinase (AMPK) (Baker et al., 1993; Liu et al., 1993; McMullen et al., 2003; Seth et al., 2009; Bostrom et al., 2010; Zhang et al., 2010). Translating stretch-stimuli to downstream signaling, the mechanosensing apparatus is controlled by transient receptor potential (TRP) channels, integrins and various z-disc associated proteins such as muscle LIM protein (MLP), actinin-associated LIM protein (ALP) and Nebulette (NEB) as well as the sarcomere-spanning protein titin (Linke, 2008; Seth et al., 2009; Frank and Frey, 2011; Luedde et al., 2011; Hamdani et al., 2013; Maillet et al., 2013). While the notion of (these) mediators as the " good guys " in cardiac remodeling seems very appealing and is founded on robust scientific work(s), a note of caution seems advisable not to fall for a false dichotomy bearing in mind what Paracelsus postulated about 500 years ago: " Dosis sola venenum facit " (Shiojima et al., 2005; Hill and Olson, 2008; Tham et al., 2015). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Cardiac remodeling describes the heart's multimodal response to a myriad of external or intrinsic stimuli and stressors most of which are probably only incompletely elucidated to date. Over many years the signaling molecules involved in these remodeling processes have been dichotomized according to a classic antagonistic view of black and white, i.e., attributed either a solely maladaptive or entirely beneficial character. By dissecting controversies, recent developments and shifts in perspective surrounding the three major cardiac signaling molecules calcineurin (Cn), protein kinase A (PKA) and calcium/calmodulin-dependent kinase II (CaMKII), this review challenges this dualistic view and advocates the nature and dignity of each of these key mediators of cardiac remodeling as a multilayered, highly context-sensitive and sophisticated continuum that can be markedly swayed and influenced by a multitude of environmental factors and crosstalk mechanisms. Furthermore this review delineates the importance and essential contributions of degradation and proteolysis to cardiac plasticity and homeostasis and finally aims to integrate the various aspects of protein synthesis and turnover into a comprehensive picture.
    Frontiers in Physiology 08/2015; 6:202. DOI:10.3389/fphys.2015.00202 · 3.53 Impact Factor
  • Source
    • "Calcium pathways to activate transcription pathways for Ca 2+ release from cellular organelles. Preferentially localized to the peripheral plasma membrane in cardiomyocytes (Kuwahara et al., 2006; Seth et al., 2009; Wu et al., 2010), they are cation-selective channels that initiate cardiac hypertrophy by Ca 2+ influx and subsequent Cn activation (Bush et al., 2006; Kuwahara et al., 2006; Nakayama et al., 2006; Onohara et al., 2006). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Ca(2+) is probably the most versatile signal transduction element used by all cell types. In the heart, it is essential to activate cellular contraction in each heartbeat. Nevertheless Ca(2+) is not only a key element in excitation-contraction coupling (EC coupling), but it is also a pivotal second messenger in cardiac signal transduction, being able to control processes such as excitability, metabolism, and transcriptional regulation. Regarding the latter, Ca(2+) activates Ca(2+)-dependent transcription factors by a process called excitation-transcription coupling (ET coupling). ET coupling is an integrated process by which the common signaling pathways that regulate EC coupling activate transcription factors. Although ET coupling has been extensively studied in neurons and other cell types, less is known in cardiac muscle. Some hints have been found in studies on the development of cardiac hypertrophy, where two Ca(2+)-dependent enzymes are key actors: Ca(2+)/Calmodulin kinase II (CaMKII) and phosphatase calcineurin, both of which are activated by the complex Ca(2+)/Calmodulin. The question now is how ET coupling occurs in cardiomyocytes, where intracellular Ca(2+) is continuously oscillating. In this focused review, we will draw attention to location of Ca(2+) signaling: intranuclear ([Ca(2+)](n)) or cytoplasmic ([Ca(2+)](c)), and the specific ionic channels involved in the activation of cardiac ET coupling. Specifically, we will highlight the role of the 1,4,5 inositol triphosphate receptors (IP(3)Rs) in the elevation of [Ca(2+)](n) levels, which are important to locally activate CaMKII, and the role of transient receptor potential channels canonical (TRPCs) in [Ca(2+)](c), needed to activate calcineurin (Cn).
    Frontiers in Physiology 11/2012; 3:452. DOI:10.3389/fphys.2012.00452 · 3.53 Impact Factor
  • Source
    • "Why others [6] [7] have found an important role for these channels in the induction of pathological hypertrophy is unclear. TRP channel expression is increased in hearts with pathological stress and their presence has been linked to the induction and maintenance of pathological hypertrophy [8] [64]. The mechanism by which these channels induce pathological hypertrophy is unclear, at least to us, but is thought to involve Ca 2+ influx through the TRP channels [8] [9] [10]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Common cardiovascular diseases such as hypertension and myocardial infarction require that myocytes develop greater than normal force to maintain cardiac pump function. This requires increases in [Ca(2+)]. These diseases induce cardiac hypertrophy and increases in [Ca(2+)] are known to be an essential proximal signal for activation of hypertrophic genes. However, the source of "hypertrophic" [Ca(2+)] is not known and is the topic of this study. The role of Ca(2+) influx through L-type Ca(2+) channels (LTCC), T-type Ca(2+) channels (TTCC) and transient receptor potential (TRP) channels on the activation of calcineurin (Cn)-nuclear factor of activated T cells (NFAT) signaling and myocyte hypertrophy was studied. Neonatal rat ventricular myocytes (NRVMs) and adult feline ventricular myocytes (AFVMs) were infected with an adenovirus containing NFAT-GFP, to determine factors that could induce NFAT nuclear translocation. Four millimolar Ca(2+) or pacing induced NFAT nuclear translocation. This effect was blocked by Cn inhibitors. In NRVMs Nifedipine (Nif, LTCC antagonist) blocked high Ca(2+)-induced NFAT nuclear translocation while SKF-96365 (TRP channel antagonist) and Nickel (Ni, TTCC antagonist) were less effective. The relative potency of these antagonists against Ca(2+) induced NFAT nuclear translocation (Nif>SKF-96365>Ni) was similar to their effects on Ca(2+) transients and the LTCC current. Infection of NRVM with viruses containing TRP channels also activated NFAT-GFP nuclear translocation and caused myocyte hypertrophy. TRP effects were reduced by SKF-96365, but were more effectively antagonized by Nif. These experiments suggest that Ca(2+) influx through LTCCs is the primary source of Ca(2+) to activate Cn-NFAT signaling in NRVMs and AFVMs. While TRP channels cause hypertrophy, they appear to do so through a mechanism involving Ca(2+) entry via LTCCs.
    Journal of Molecular and Cellular Cardiology 08/2012; 53(5):657-67. DOI:10.1016/j.yjmcc.2012.08.005 · 4.66 Impact Factor
Show more