Stretch-activated TRPV2 channels: Role in mediating cardiopathies

https://doi.org/10.1016/j.pbiomolbio.2017.05.007Get rights and content

Abstract

Transient receptor potential vanilloid type 2, TRPV2, is a calcium-permeable cation channel belonging to the TRPV channel family. Although this channel has been first characterized as a noxious heat sensor, its mechanosensor property recently gained importance in various physiological functions. TRPV2 has been described as a stretch-mediated channel and a regulator of calcium homeostasis in several cell types and has been shown to be involved in the stretch-dependent responses in cardiomyocytes. Hence, several studies in the last years support the idea that TRPV2 play a key role in the function and structure of the heart, being involved in the cardiac compensatory mechanisms in response to pathologic or exercise-induced stress. We present here an overview of the current literature and concepts of TRPV2 channels involvement (i) in the mechanical coupling mechanisms in heart and (ii) in the mechanisms that lead to cardiomyopathies. All these studies lead us to think that TRPV2 may also be an important cardiac drug target based on its major physiological roles in heart.

Introduction

The mammalian TRP channel superfamily is classified into six subfamilies with high sequence similarity. The TRPV (Vanilloid) subfamily, is divided in two groups, based on their sequence homology: TRPV1-4 and TRPV5-6 (see for review, Shibasaki, 2016). The channels belonging to the first group present temperature-evoked currents when they are expressed in heterologous cell system. Their range of activation is comprised between ∼25 °C for TRPV4 and ∼52 °C for TRPV2. Nevertheless, any physiological role in temperature sensing has been proved for TRPV2 and experiments with TRPV2 knockout mice showed a similar response to thermal stimulus with WT mice (Park et al., 2011).

Two groups, almost simultaneously, identified TRPV2 in 1999, using different approaches. Caterina et al. (1999), in the aim to identify new proteins involved in the detection of noxious stimuli by sensory neurons have searched for the sequences related to TRPV1 (VR1) in the GenBank database. They found orthologues in human and mouse of the same protein, which they named vanilloid-receptor-like protein 1 (VRL-1). Their experiments on transfected HEK 293 cells demonstrated that VRL-1 does not response to capsaicin, acid or moderate heat as seen with VR1 but activated by high temperature (>52 °C). They also demonstrated in oocytes of Xenopus that this channel could mediate cationic currents with higher divalent permeability (P) (Ca2+ > Mg2+ > Na+ ∼ Cs+ ∼ K+; PCa2+/PNa+ = 2.94; PMg2+/PNa+ = 2.40).

Kanzaki et al. (1999) also identified in mouse tissues, a calcium permeable cation channel with 79.4% of similarity with VRL-1 and presenting a 2.824 base pairs in length, predicting a protein of 756 amino acids length with a relative molecular mass of 86 k Da. This channel was found to be regulated by Insulin-like growth factor-1 (IGF-1) and was named Growth-factor-Regulated Channel (GRC). When transfected in CHO cells, a gradually increase of cytosolic [Ca2+] was observed after treatment with IGF-1. They also showed that this channel is normally localized in intracellular compartments but can be translocated to plasma membrane after IGF-1 or other growth factors treatments such as platelet-derived growth factor (PDGF) or Fetal Calf Serum (FCS). Then TRPV2 was described as a homotetrameric N-glycosylated protein that translocates from intracellular membrane compartments to the plasma membrane after stimulation of the phosphatidylinositol 3-kinase (PI3K) and other kinase signaling pathways (Perálvarez-Marín et al., 2013).

Taking into account that TRPV2 expression was found in many non-neuronal tissues (Shibasaki, 2016), the physiological roles of TRPV2 go far beyond the perception of noxious stimuli, particularly through its membrane stretch-dependent properties. In this review, we will focus on the unique characteristics of TRPV2 as a mechanosensor and its role in both in the mechano-electric coupling in cardiac tissue and in heart diseases.

Section snippets

TRPV 2: an ubiquitous mechanosensor

Among the functions assigned to TRPV2, the mechanosensitive property has emerged. Mechanosensitive channels are currently considered as major mechanosensors transducing mechanical stimuli exerted on membranes of living cells into electrical or chemical intracellular signals (Gillespie and Walker, 2001, Hamill and Martinac, 2001). These types of channels can switch from “closed” to “open” state in response to stretch alone or to a direct mechanical membrane deformation (see for review: Reed

Exploration of the stretch-activation of TRPV2 channels

Different methods have been used to explore the involvement of TRPV2 in the mechanical response. The most common is the hypoosmotick shock. Indeed, perfusion of a hypotonic solution triggers cell swelling through water entry, which is necessary for the balancing of ionic gradients between the extracellular medium and the cytosolic compartment. The consequent increase of cell volume can provide a three-dimensional stretch of the cell, but changes in volume were not easily related to changes in

TRPV2 modulation and cardiac function

In 2003, it was reported for the first time that the TRPV2 channel, named at that time the growth factor regulated channel (GRC), was expressed in cardiac cells (Iwata et al., 2003). TRPV2 was found around 10 fold more abundant in cardiac than in skeletal muscle with a prominent expression in intercalated discs. Then, later, TRPV2 channels have been presented as molecular candidates for cardiac stretch-activated ion channels (Reed et al., 2014) because their mechanosensitivity was characterized

Stretch-activation mechanisms?

Mechanisms involved in opening TRPV2 by membrane stretch have not yet been determined. Nevertheless, the intracellular N-terminal domain of TRPV channels contains multiple ankyrin repeats and it has been demonstrated for TRPV4 that deletion of ankyrin repeats abolished heat activation of the channel (Watanabe et al., 2002). Ankyrin repeats domain is a common motif involved in protein–protein recognition, mediating a diverse range of functions, including ion transport, cell–cell signaling,

The critical point of stretch-dependent TRPV2 location

From the beginning of the discovery of TRPV2 channel in cardiac cells (Iwata et al., 2003), it has been hypothesized that this channel localizes mainly in intracellular pools under basal conditions and that it could translocate upon stimulation with growth factors, through the PI3K pathway, as it has been observed in other cells (Kanzaki et al., 1999, Dogra et al., 2006, Aoyagi et al., 2010). Indeed, TRPV2 translocation was found to occur in response to IGF-1 but also to a cyclic stretch of 20%

Functional relationship with other TRPs channels

As TRPV2 and TRPC1 expression was significantly higher in DCM, this raises the question about a functional relationship between TRPV2 and other TRPs channels, and particularly TRPCs, under physiological and pathophysiological conditions. There are several cases of TRPs-dependent TRPs activation. Indeed, Chaudhuri et al. (2008) reported a mechanism in which TRPC6 activation initiates a cascade resulting in TRPC5 translocation when endothelial cells are incubated in lysophosphatidylcholine. As

TRPV2 variants in dilated cardiomyopathy?

In some studies (Muraki et al., 2003, Aguettaz et al., 2016b), the presence of a light band in mdx TRPV2 western blots seems to indicate the expression of two different proteins and makes possible the presence of a TRPV2 variant expression. This phenomenon was already observed with others TRPV channels (Sharif Naeini et al., 2006, Sudbury et al., 2010). Indeed, it has already been demonstrated that osmosensensory transduction in mouse supraoptic nucleus neurons is depending on an N-terminal

Conclusion

The TRPV2 channel tissue distribution is quite broad and the cellular signaling pathways that regulate its function seem to show more tissue-specific variations. In this review, we focused on the physiological importance of TRPV2 ion channels through their mechanosensor properties in the heart. Evidence is made that the TRPV2 proteins form a part of cardiac stretch activated channels and the major role of TRPV2 channels in the cardiac dystrophic Ca2+ signaling pathology is demonstrated.

Conflict of interest

None declared.

Acknowledgments

This work was supported by grants from the Association Française contre les Myopathies-Telethon. We thanks the imaging Platform ImageUP for its technical assistance.

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