Role of Known Transient Receptor Potential Vanilloid Channels in Modulating Cardiac Mechanobiology

The transient receptor potential (TRP) channels have been described in almost every mammalian cell type. Several members of the Vanilloid (TRPV) subtype have been found to play important roles in modulating cardiac structure and function through Ca2+ handling in response to systemic and local mechanobiological cues. In this review, we will consider the most studied TRPV channels in the cardiovascular field; transient receptor potential vanilloid 1 as a modulator of cardiac hypertrophy; transient receptor potential vanilloid 2 as a structural and functional protein; transient receptor potential vanilloid 3 in the development of hypertrophy and myocardial fibrosis; and transient receptor potential vanilloid 4 in its roles modulating the fibrotic and functional responses of the heart to pressure overload. Lastly, we will also review the potential overlapping roles of these channels with other TRP proteins as well as the advances in translational and clinical arenas associated with TRPV channels.

Modern concepts of the role of transient receptor potential channel vanilloid subfamily (TRPV) in development osmotic airway hyperresponsiveness in asthma patients (review)

Introduction. Airway hyperresponsiveness to osmotic stimuli is often found among patients with asthma. It is assumed that the transient receptor potential channels of vanilloid subfamily (TRPV) may play a key role in the onset of this phenomenon.Aim. Review of modern world literature data on osmotic airway hyperresponsiveness and the role of TRPV channels in its development.Materials and methods. This review summarizes the data from articles published over the past five years found in PubMed and Google Scholar. However, earlier publications were also included if necessary.Results. The influence of natural osmotic triggers on the formation of bronchoconstriction in patients with asthma has been demonstrated. The effects that occur in the airways, depending on the functional state of TRPV1, TRPV2 and TRPV4 osmosensitive receptors are described, and the mechanisms that mediate the development of bronchial hyperresponsiveness with the participation of these channels are partially disclosed.Conclusion. It is safe to assume that TRPV channels are directly or indirectly associated with airway hyperresponsiveness to osmotic stimuli. Signaling cascades triggered by TRPV activation largely explain the effects of osmotic influence on the airways and the occurrence of bronchoconstriction. It could be suggested that TRPV1 signaling mediates the development of bronchospasm to hyperosmolar stimuli, while TRPV2 and TRPV4 are most likely involved in hypoosmotic-induced bronchoconstriction. Further study of the role of TRPV1, TRPV2 and TRPV4 in osmotic airway hyperresponsiveness is relevant and promising in terms of pharmacological management of this condition.

Molecular Properties of Ca2+ Transport Through TRPV2 Channel: A Molecular Dynamic Simulations Study

TRPV channels are a category of nonselective cation channels that activated by heat and ligands, and permeate monovalent and divalent ions. The mechanism of Ca2+ transfer through TRPV2 channel is not well known. Here, we investigated the reaction coordination and energy fluctuation of Ca2+ transition in TRPV2 channel by steered molecular dynamics (SMD) simulations and potential of mean force (PMF) calculation. Results showed that electrostatic interactions between Ca2+ and residues of the first and second gates had main roles in ions transfer through the channel, and also, we recognized important amino acids in this path. Moreover, results indicated that enter and exit of calcium ions needed to overcome barrier energies in first and second gates.

Comparative Analysis of Single-Molecule Dynamics of TRPV1 and TRPV4 Channels in Living Cells

TRPV1 and TRPV4, members of the transient receptor potential vanilloid family, are multimodal ion channels activated by various stimuli, including temperature and chemicals. It has been demonstrated that TRPV channels function as tetramers; however, the dynamics of the diffusion, oligomerization, and endocytosis of these channels in living cells are unclear. Here we undertook single-molecule time-lapse imaging of TRPV1 and TRPV4 in HEK 293 cells. Differences were observed between TRPV1 and TRPV4 before and after agonist stimulation. In the resting state, TRPV4 was more likely to form higher-order oligomers within immobile membrane domains than TRPV1. TRPV1 became immobile after capsaicin stimulation, followed by its gradual endocytosis. In contrast, TRPV4 was rapidly internalized upon stimulation with GSK1016790A. The selective loss of immobile higher-order oligomers from the cell surface through endocytosis increased the proportion of the fast-diffusing state for both subtypes. With the increase in the fast state, the association rate constants of TRPV1 and TRPV4 increased, regenerating the higher-order oligomers. Our results provide a possible mechanism for the different rates of endocytosis of TRPV1 and TRPV4 based on the spatial organization of the higher-order structures of the two TRPV channels.

Beyond Hot and Spicy: TRPV Channels and their Pharmacological Modulation

Transient receptor potential vanilloid (TRPV) channels are part of the TRP channel superfamily and named after the first identified member TRPV1, that is sensitive to the vanillylamide capsaicin. Their overall structure is similar to the structure of voltage gated potassium channels (Kv) built up as homotetramers from subunits with six transmembrane helices (S1-S6). Six TRPV channel subtypes (TRPV1-6) are known, that can be subdivided into the thermoTRPV (TRPV1-4) and the Ca2+-selective TRPV channels (TRPV5, TRPV6). Contrary to Kv channels, TRPV channels are not primary voltage gated. All six channels have distinct properties and react to several endogenous ligands as well as different gating stimuli such as heat, pH, mechanical stress, or osmotic changes. Their physiological functions are highly diverse and subtype as well as tissue specific. In many tissues they serve as sensors for different pain stimuli (heat, pressure, pH) and contribute to the homeostasis of electrolytes, the maintenance of barrier functions and the development of macrophages. Due to their fundamental role in manifold physiological and pathophysiological processes, TRPV channels are promising targets for drug development. However, drugs targeting specific TRPV channels, that are suitable for drug therapy, are rare. Moreover, selective and potent compounds for further research at TRPV channels are often lacking. In this review different aspects of the structure, the different gating stimuli, the expression pattern, the physiological and pathophysiological roles as well as the modulating mechanisms of synthetic, natural and endogenous ligands are summarized.

Transient Receptor Potential Vanilloid in the Brain Gliovascular Unit: Prospective Targets in Therapy

The gliovascular unit (GVU) is composed of the brain microvascular endothelial cells forming blood–brain barrier and the neighboring surrounding “mural” cells (e.g., pericytes) and astrocytes. Modulation of the GVU/BBB features could be observed in a variety of vascular, immunologic, neuro-psychiatric diseases, and cancers, which can disrupt the brain homeostasis. Ca2+ dynamics have been regarded as a major factor in determining BBB/GVU properties, and previous studies have demonstrated the role of transient receptor potential vanilloid (TRPV) channels in modulating Ca2+ and BBB/GVU properties. The physiological role of thermosensitive TRPV channels in the BBB/GVU, as well as their possible therapeutic potential as targets in treating brain diseases via preserving the BBB are reviewed. TRPV2 and TRPV4 are the most abundant isoforms in the human BBB, and TRPV2 was evidenced to play a main role in regulating human BBB integrity. Interspecies differences in TRPV2 and TRPV4 BBB expression complicate further preclinical validation. More studies are still needed to better establish the physiopathological TRPV roles such as in astrocytes, vascular smooth muscle cells, and pericytes. The effect of the chronic TRPV modulation should also deserve further studies to evaluate their benefit and innocuity in vivo.

Effect of Alpha-Glucosyl-Hesperidin Consumption on Lens Sclerosis and Presbyopia

Presbyopia is characterized by a decline in the ability to accommodate the lens. The most commonly accepted theory for the onset of presbyopia is an age-related increase in the stiffness of the lens. However, the cause of lens sclerosis remains unclear. With age, water microcirculation in the lens could change because of an increase in intracellular pressure. In the lens, the intracellular pressure is controlled by the Transient Receptor Potential Vanilloid (TRPV) 1 and TRPV4 feedback pathways. In this study, we tried to elucidate that administration of α-glucosyl-hesperidin (G-Hsd), previously reported to prevent nuclear cataract formation, affects lens elasticity and the distribution of TRPV channels and Aquaporin (AQP) channels to meet the requirement of intracellular pressure. As a result, the mouse control lens was significantly toughened compared to both the 1% and 2% G-Hsd mouse lens treatments. The anti-oxidant levels in the lens and plasma decreased with age; however, this decrease could be nullified with either 1% or 2% G-Hsd treatment in a concentration- and exposure time-dependent manner. Moreover, G-Hsd treatment affected the TRPV4 distribution, but not TRPV1, AQP0, and AQP5, in the peripheral area and could maintain intracellular pressure. These findings suggest that G-Hsd has great potential as a compound to prevent presbyopia and/or cataract formation.

OSM-9 and OCR-2 TRPV channels are accessorial warm receptors in Caenorhabditis elegans temperature acclimatisation

Caenorhabditis elegans (C. elegans) exhibits cold tolerance and temperature acclimatisation regulated by a small number of head sensory neurons, such as the ADL temperature-sensing neurons that express three transient receptor potential vanilloid (TRPV) channel subunits, OSM-9, OCR-2, and OCR-1. Here, we show that an OSM-9/OCR-2 regulates temperature acclimatisation and acts as an accessorial warmth-sensing receptor in ADL neurons. Caenorhabditis elegans TRPV channel mutants showed abnormal temperature acclimatisation. Ectopic expression of OSM-9 and OCR-2 in non-warming-responsive gustatory neurons in C. elegans and Xenopus oocytes revealed that OSM-9 and OCR-2 cooperatively responded to warming; however, neither TRPV subunit alone was responsive to warming. A warming-induced OSM-9/OCR-2-mediated current was detectable in Xenopus oocytes, yet ADL in osm-9 ocr-2 double mutant responds to warming; therefore, an OSM-9/OCR-2 TRPV channel and as yet unidentified temperature receptor might coordinate transmission of temperature signalling in ADL temperature-sensing neurons. This study demonstrates direct sensation of warming by TRPV channels in C. elegans.