Kanchan Kulkarni
Richard D. Walton
Sebastien Chaigne- 1IHU Liryc, INSERM, U1045, CRCTB, University Bordeaux, Bordeaux, France
- 2CHU de Bordeaux, Cardiology, INSERM, U1045, CRCTB, Bordeaux, France
Introduction
Cardiovascular disease remains the leading global cause of mortality, underscoring the urgent need to better understand the mechanisms driving cardiac dysfunction (Jagannathan et al., 2019). Ion channels are key regulators of cardiac excitability, and among them, the transient receptor potential (TRP) family has gained attention for its diverse physiological roles. TRP channels are ubiquitously expressed in mammalian hearts and function as essential “cellular switches” that respond to a wide range of chemical and physical stimuli, influencing sensory physiology (Hof et al., 2019; Zhang et al., 2023). Comprising 28 members across six subfamilies, TRP channels act as polymodal sensors responding to chemical, thermal, and mechanical cues. In the heart, these channels influence calcium (Ca2+) dynamics, electrical conduction, mechanical responsiveness, and stress adaptation (Hof et al., 2019).
Building on the foundational discoveries by Drs. David Julius and Ardem Patapoutian on temperature and mechanotransduction pathways—work that earned the 2021 Nobel Prize in Physiology or Medicine—there is growing recognition of TRP channels’ roles beyond sensory systems, including cardiovascular physiology and pathophysiology (Caterina et al., 1997; Peier et al., 2002). In particular, genetically modified knockout (KO) mice models have emerged as powerful tools to explore TRP channel functions in cardiac tissue, allowing for precise dissection of their mechanistic roles in disease progression and therapeutic potential. This opinion letter highlights key advances and future directions in further leveraging TRP KO models to unlock the therapeutic promise of TRP channels in cardiac health.
Cardiac TRP channels: multifaceted roles and research frontiers
TRP channels regulate numerous cardiac functions, including rhythm generation, Ca2+ handling, contractility, and responses to mechanical stress (Hof et al., 2016; Chaigne et al., 2023; Hu et al., 2023; Veteto et al., 2020). Several family members (e.g., TRPC6, TRPM4, TRPV4) have been implicated in arrhythmogenesis, hypertrophy, fibrosis, and ischemia-reperfusion injury. Their broad permeability to cations and ability to integrate diverse stimuli render them critical for both normal physiology and pathological remodeling (Numata et al., 2016; Guo et al., 2024). In physiological conditions, inward current through these channels is primarily due to the entry of Ca2+, sodium (Na+), or magnesium (Mg2+), while outward current results from potassium (K+) exiting the cell. Notably, very little is known about Mg2+ handling in relation to TRP channel activities and heart function, even though mutations in sub-families of these channels have been shown to be associated with disturbances in Mg2+, highlighting the need for further investigations (Gwanyanya et al., 2004; Jin et al., 2022).
Activation of TRP channels typically induces a depolarizing current because the main flux of cations is inward. This characteristic makes TRP channels particularly relevant in excitable cells like cardiomyocytes, where they can prolong action potential duration, as observed following activation or potentiation of TRPC3 (Ju et al., 2015), TRPM4 (permeable to Na+) (Hof et al., 2016; Simard et al., 2013), TRPM6-7 (Gwanyanya et al., 2021) and TRPV4 (Chaigne et al., 2023). However, many TRP channels do not function as classical mechanosensors. Recent studies show that while TRPs may not be directly gated by membrane stretch (O'Neil and Heller, 2005; Nikolaev et al., 2019), they can act as mechano-effectors downstream of primary mechanosensors, including PIEZO1 channels (Guo et al., 2024; Guo et al., 2021; Yu et al., 2022). For instance, TRPV4 interacts with volume-sensitive signalling molecules such as Src kinase (Zou et al., 2022) and phospholipase A2 (Gorelick and Nathanson, 2020). These emerging insights necessitate a more nuanced classification of TRP channels in mechanotransduction.
Importantly, the effector role of TRP channels—particularly their position downstream of primary sensors—may open opportunities for more progressive and targeted therapeutic interventions. Rather than blocking upstream mechanotransduction entirely, targeting TRPs may allow fine-tuning of maladaptive downstream signalling. This approach could offer graded, context-sensitive modulation in heart failure and hypertrophy, with lower risk of disrupting physiological homeostasis. Supporting this concept, TRPC3 and TRPC6, for example, have been shown to act as calcium-permeable effectors that activate the calcineurin–NFAT pathway downstream of neurohumoral and mechanical stimuli (Seo et al., 2014). Inhibiting such TRPs may thus interrupt pro-hypertrophic signalling while preserving upstream sensory mechanisms essential for baseline cardiac function. This positions TRP channels as viable and adaptable targets for therapeutic strategies focused on disease modification without systemic disruption.
However, selective agonists and antagonists for TRP channels are scarce, with only a few known agents such as capsaicin, an agonist of TRPV1 (Caterina et al., 1997; Wang and Wang, 2005), that have undergone comprehensive pharmacological evaluation. Hence, while this approach could offer graded, context-sensitive modulation in heart failure and hypertrophy, with lower risk of disrupting physiological homeostasis, further studies are required to identify selective modulators of these channels. The use of TRP KO mice offers a potent avenue to better understand the specific roles of this ion channel family and validate the effectiveness and safety of their targeted modulators.
Advantages of knockout models in TRP research
Given the limited availability and selectivity of pharmacological modulators for TRP channels, KO mice models provide an essential approach for understanding cardiac channel-specific functions. For example, TRPM4 KO mice have clarified this channel’s role in prolonging action potentials and promoting arrhythmia in stress models (Guinamard et al., 2015). Similarly, both TRPC6 and TRPV4 KO mice resist pressure-overload-induced hypertrophy (Jia et al., 2024; Kinoshita et al., 2010; Tang et al., 2022). Interestingly, TRPM4 has emerged as a critical integrator of distinct pathological stimuli. Studies have shown that both pressure overload and Angiotensin II (AngII) stimulation activate TRPM4 through different signalling pathways (Guo et al., 2021; Kecskes et al., 2015). This convergence highlights TRPM4’s central role in cardiac disease and underscores its promise as a therapeutic target across multiple disease contexts.
A comprehensive summary of current TRP KO mice models is presented in Table 1, demonstrating the scope and complexity of the roles of these channels in cardiovascular pathophysiology. KO models offer several advantages:
• Causality: Genetic deletion isolates the contribution of individual channels to disease phenotypes.
• Compensation Insight: TRP families exhibit overlapping roles. KO studies have revealed compensatory expression among TRPC channels (Vandewauw et al., 2018), highlighting complex redundancy.
• Therapeutic Discovery: By testing drugs in KO versus wild-type mice, researchers can assess target specificity and identify off-target effects.
Table 1. TRP channel expression and properties in myocytes.
These benefits make TRP KO models a cornerstone of mechanistic cardiovascular research.
KO mice models offer an invaluable tool for uncovering new components of cellular dysfunction and their translational impacts. While clinical electrocardiogram (ECG) features such as heart rate, PR interval, QRS complex, and QT/QTc interval, are crucial for diagnosing and monitoring physiological and various cardiac conditions, in-vitro parameters, offer focused, detailed insights into the cellular and molecular mechanisms underlying cardiac electrical activity. Unitary currents, measured through single-channel recordings, reveal the behaviour of individual ion channels that contribute to the macroscopic currents linked to cellular activation profiles (Guinamard et al., 2015). For example, TRP channels dysfunction detected through unitary current recordings, can be correlated with changes in both action potential and ECG parameters (Chaigne et al., 2021), indicating a risk of arrhythmias.
While it has been suggested that mammalian TRP channels are insensitive to membrane stretch, some TRP channels respond to mechanical forces (Liu and Montell, 2015) applied to the cell membrane from external influences (see Table 1). These forces can modulate the open probability of the channels, without involving a signalling cascade. This mechanosensitivity allows TRP channels to respond to various physical stimuli such as pressure, stretch, and shear stress, thereby playing a crucial role in various physiological processes (Liu and Montell, 2015; Moran et al., 2004). KO models have been effective in investigating the mechanosensitivity of TRP channels and their down-stream effects. Furthermore, using KO mice, researchers can also explore potential compensatory mechanisms that may arise due to the absence or inhibition of targeted TRP channels. This approach provides insights into the complex interplay between different ion channels and signalling pathways in maintaining physiological homeostasis.
Finally, integrative in-vivo models can help uncover systemic effects and potential off-target effects that might not be evident in isolated cardiomyocytes which lack the full spectrum of hormonal (Liu et al., 2022), immune (Wu et al., 2023), and nervous system regulation (Shanks et al., 2019). For instance, a drug might show promise in-vitro but could interact with other physiological systems in-vivo, leading to unforeseen side-effects. Comprehensive in-vivo testing can thus, identify early issues in the drug development process, saving time and resources. Through transesophageal stimulation, which enables the analysis of underlying mechanisms of cardiac rhythm disorders across the heart’s chambers, the use of KO models, helps to indirectly establish a link between the absence of a gene and its involvement in the development of arrhythmia. Note that this approach may not be ideal for mechanical ion channels that are sensitive to stretching. Ultimately, the absence of the gene of interest can indirectly enhance our understanding of the mechanisms underlying cardiac tissue hypertrophy and fibrosis (Guo et al., 2021; Zou et al., 2022; Watanabe et al., 2013).
Future directions and strategic areas for therapeutic insight
Several innovative approaches are currently under development and have the potential to pioneer change in cardiac research. A key strategy involves structure-based drug design, which aims to create highly specific inhibitors by targeting the three-dimensional TRP channels structure. Another promising technique, Surface Plasmon Resonance (SPR), provides real-time insights into how these inhibitors interact with TRP channels, enhancing our understanding of their binding mechanisms. Their thorough investigation could lead to new therapeutic approaches for treating cardiovascular abnormalities. Main takeaways that could influence future therapeutic strategies are outlined below:
1. Mechanotransduction and Heart Failure: Mechanosensitive TRP channels (e.g., TRPC6 (Onohara et al., 2006), TRPM7 (Yu et al., 2014), TRPV4 (Veteto et al., 2020)) are activated under pathological stretch, making them promising targets in heart failure. KO models subjected to pressure overload can dissect these channels’ contributions to maladaptive remodelling.
2. Sudden Cardiac Death and Arrhythmia: TRPA1 (Conklin et al., 2019) and TRPM4 (Vandewiele et al., 2022; Yang et al., 2006) KO mice exhibit resistance to arrhythmia under stress or ischemic conditions. TRP channels modulating action potential duration are ideal candidates for anti-arrhythmic drug development.
3. Inter-individual Variability in Drug Response: KO models help reveal how TRP channel expression variability influences therapeutic outcomes. For example, TRPC3 (Kitajima et al., 2016) and TRPM2 are stress-responsive and may contribute to variable responses to oxidative or hypertrophic stimuli (Onohara et al., 2006; Kitajima et al., 2016; Takahashi et al., 2012; Chen et al., 2013).
4. Brain-Heart Axis and Neurogenic Modulation: With expression in sensory neurons and cardiac tissue, channels like TRPM8 and TRPV1 (Yoshie et al., 2020) may mediate autonomic effects on the heart (Shanks et al., 2019; Yin et al., 2024). TRP KO models enable investigation into neuro-cardiac interactions and their therapeutic modulation.
5. Translation to Human Therapies: Though interspecies differences exist, KO mice remain critical in screening for TRP-targeted therapies, particularly where pharmacological tools are lacking or non-selective. Caution is needed when extrapolating findings, but the insights remain invaluable.
Limitations and integration with complementary models
While KO mice are indispensable, they have limitations. Genetic deletion can trigger compensatory mechanisms, masking functional deficits. Moreover, mouse cardiac electrophysiology differs from humans in ion channel expression and repolarization dynamics (Joukar, 2021). These differences, including variations in immune system responses (Gilbertson and Weinmann, 2021), can undeniably impact the relevance of findings to human clinical settings. In this case, human tissue or cellular models, offer promising alternatives. Additionally, while not all TRP channels can compensate for one another, functional redundancy within the TRP family has been documented. For example, research has shown that the presence of at least one of these channels (TRPA1, TRPM3 or TRPV1) helps preserve somatosensory heat responsiveness (Vandewauw et al., 2018). These compensatory effects must be carefully considered when interpreting KO model data.
To address these challenges, future studies could incorporate the following complementary strategies:
• Integrate human iPSC-derived cardiomyocytes and organoids
• Employ computational modelling of TRP-mediated currents
• Combine TRP KOs with spatial omics and functional imaging
These approaches could provide a comprehensive understanding of TRP channel function across species and contexts.
Conclusion
Cardiac TRP channels are emerging as pivotal regulators of cardiovascular physiology and pathology. KO mice models offer a unique opportunity to define their functions, explore disease mechanisms, and identify new therapeutic strategies. By refining our understanding of TRP channel biology, particularly through the lens of mechanotransduction and electrophysiology, the next-generation of targeted interventions may be realized. We advocate for a continued, strategic use of TRP KO models as a springboard for precision cardiovascular medicine.
Author contributions
KK: Conceptualization, Writing – review and editing. RW: Conceptualization, Writing – review and editing. SC: Conceptualization, Supervision, Writing – original draft.
Funding
The author(s) declare that financial support was received for the research and/or publication of this article. This work was supported by the French Government as part of the “Investments of the Future,” National Research Agency (ANR), Grant reference ANR-10-IAHU-04.
Conflict of interest
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision.
Generative AI statement
The author(s) declare that no Generative AI was used in the creation of this manuscript.
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Keywords: TRP channels, knockout (KO) mice, cardiac physiology, cardiac pathology, calcium homeostasis
Citation: Kulkarni K, Walton RD and Chaigne S (2025) Unlocking the potential of cardiac TRP channels using knockout mice models. Front. Physiol. 16:1585356. doi: 10.3389/fphys.2025.1585356
Received: 28 February 2025; Accepted: 07 April 2025;
Published: 17 April 2025.
Edited by:
Deniz Yilmazer-Hanke, University of Ulm, GermanyReviewed by:
James Henry Peters, Washington State University, United StatesPraghalathan Kanthakumar, University of Missouri, United States
Yang Guo, Victor Chang Cardiac Research Institute, Australia
Copyright © 2025 Kulkarni, Walton and Chaigne. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
*Correspondence: Sebastien Chaigne, c2ViYXN0aWVuLmNoYWlnbmVAaWh1LWxpcnljLmZy