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.

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    • "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). "
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    • "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). "
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    • "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]. "
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