The Multifaceted Functions of TRPV4 and Calcium Oscillations in Tissue Repair

Abstract

The transient receptor potential vanilloid 4 (TRPV4) specifically functions as a mechanosensitive ion channel and is responsible for conveying changes in physical stimuli such as mechanical stress, osmotic pressure, and temperature. TRPV4 enables the entry of cation ions, particularly calcium ions, into the cell. Activation of TRPV4 channels initiates calcium oscillations, which trigger intracellular signaling pathways involved in a plethora of cellular processes, including tissue repair. Widely expressed throughout the body, TRPV4 can be activated by a wide array of physicochemical stimuli, thus contributing to sensory and physiological functions in multiple organs. This review focuses on how TRPV4 senses environmental cues and thereby initiates and maintains calcium oscillations, critical for responses to organ injury, tissue repair, and fibrosis. We provide a summary of TRPV4-induced calcium oscillations in distinct organ systems, along with the upstream and downstream signaling pathways involved. In addition, we delineate current animal and disease models supporting TRPV4 research and shed light on potential therapeutic targets for modulating TRPV4-induced calcium oscillation to promote tissue repair while reducing tissue fibrosis.

Keywords: TRPV4; calcium oscillations; fibrosis; tissue repair.

Figure 1

Protein and channel structure of TRPV4. (A) Protein structure of TRPV4. TRPV4 contains the N-terminal part, six transmembrane domains, and the C-terminal part. Ca²⁺-calmodulin complex binds to the calmodulin-binding domain. The fifth and sixth transmembrane domains (TM5, TM6) form the ion-conduction pore. (B) Structure of TRPV4 channel consisting of four monomers. PIBS: phosphoinositide-binding site. PRD, proline-rich domain; ANKs, ankyrin repeats; ARS-L, arachidonate-like recognition sequence; TM1–TM6, transmembrane domains; CaMBD, calmodulin-binding domain; OMD, oligomerization domain; PDZ-L, PDZ-like domain.

Figure 2

TRPV4 mediated signaling pathways. (A) TRPV4 signaling in tissue repair. Ca²⁺ influx through Piezo channel activates PLA2 with elevated production of EET. EET sensitizes TRPV4 activation in response to mechanical cues. TRPV4-evoked Ca²⁺ influx and subsequent Ca²⁺ oscillation activate downstream YAP/TAZ to promote myofibroblast (MyoFb) differentiation. (B) TRPV4 signaling in tissue fibrosis. TGF-βR activation induces PI3K, leading to Ca²⁺ influx via TRPV4. Ca²⁺ signal further activates Rho/Rho kinases, inhibiting matrix degradation via PAI-1, and upregulating fibrotic gene expression via p38-MAPK. TRPV4-induced Ca²⁺ signal also interacts with NOX4 to promote ROS production and nuclear translocation of MRTF-A, the coactivator of α-SMA expression. PLA2, phospholipase A2; EET, epoxieicosatrienoic acids; YAP/TAZ, yes-associated protein/transcriptional coactivator; MyoFb, Myofibroblast; PI3K, phosphatidylinositol 3-kinase; PAI-1, plasminogen activator inhibitor 1; MAPK, mitogen-activated protein kinases; NOX4, NADPH Oxidase 4; ROS, reactive oxygen species; MRTF-A, myocardin-related transcription factor A.

Figure 3

TRPV4-evoked calcium oscillations. (A) Ca²⁺ oscillation induced by TRPV4 under normal circumstances. TRPV4-mediated Ca²⁺ influx activates IP₃R at ER membrane, which controls Ca²⁺ release and uptake from intracellular Ca²⁺ storage. (B) When the mitochondrial membrane potential is impaired due to increased ROS level, TRPV4 activation provokes ATP release through pannexin hemichannels. Released ATP binds P2Y receptors or adenosine resulted from ATP degradation bounds to G_i/0-coupled A₁R or G_q/11-coupled A_2BR, activates PLC, which converts PIP₂ to IP₃. IP3 binds to IP₃R channels on ER initiating calcium oscillation. IP₃, 1,4,5-trisphosphate; IP₃R, IP₃ receptor; P2Y: purinergic receptor; PLC, phospholipase C; PIP₂, Phosphatidylinositol 4,5-bisphosphate; A₁R: adenosine A₁ receptor. A_2BR: adenosine A_2B receptor.

Figure 4

Functions of TRPV4-induced Ca²⁺ oscillations across different organs. TRPV4 is essential for physiological activities in the skin, lung, cardiovascular, skeletal, nervous and reproductive systems. Fb, fibroblast; MyoFb, myofibroblast; Phos, phosphorylation; HSV, Herpes simplex virus. Upward arrows indicate higher expression or activity.