TRPing on Cell Swelling - TRPV4 Senses It

Abstract

The transient receptor potential vanilloid 4 channel (TRPV4) is a non-selective cation channel that is widely expressed and activated by a range of stimuli. Amongst these stimuli, changes in cell volume feature as a prominent regulator of TRPV4 activity with cell swelling leading to channel activation. In experimental settings based on abrupt introduction of large osmotic gradients, TRPV4 activation requires co-expression of an aquaporin (AQP) to facilitate such cell swelling. However, TRPV4 readily responds to cell volume increase irrespectively of the molecular mechanism underlying the cell swelling and can, as such, be considered a sensor of increased cell volume. In this review, we will discuss the proposed events underlying the molecular coupling from cell swelling to channel activation and present the evidence of direct versus indirect swelling-activation of TRPV4. With this summary of the current knowledge of TRPV4 and its ability to sense cell volume changes, we hope to stimulate further experimental efforts in this area of research to clarify TRPV4's role in physiology and pathophysiology.

Keywords: TRPV4 (transient receptor potential vanilloid 4); aquaporins (AQPs); osmo-sensing; volume regulation; volume-sensitive channels.

Figure 1

TRPV4 does not modulate astrocytic regulatory volume decrease following activity evoked astrocyte volume dynamics. Electrical stimulation of acute hippocampal slices from rats results in neuronal activity associated with a [K⁺]_o transient that leads to a brief change in cell volume of nearby astrocytic structures without application of an osmotic gradient to the test solution. Graphs illustrate a representative recording and summarized volume decay rates of the activity-evoked extracellular space dynamics in the absence or presence of a TRPV4 inhibitor [1 µM HC067047, same results obtained with the less specific TRPV4 inhibitor ruthenium red (1 µM)]. ns, not significant. Modified from (37) with permission.

Figure 2

TRPV4 is activated by increased cell volume. Oocytes expressing TRPV4 alone (top traces) did not swell when exposed to a hyposmotic gradient (-100 mOsm) and did not respond with TRPV4-mediated currents during this challenge. Oocytes co-expressing TRPV4 and AQP4 (bottom traces) responded to the osmotic challenge with an abrupt volume increase and a resultant large membrane current (summarized in right panel). Modified from (32) with permission.

Figure 3

TRPV4 is activated by cell swelling, independently of AQPs and osmotic gradients. The water-transporting cotransporter NKCC1, co-expressed with TRPV4 in Xenopus oocytes, was activated by exposure to K⁺ (15 mM, equimolar replacement of Na⁺). This transporter activation led to a rapid volume increase (left panel) in the absence of an external introduction of an osmotic gradient. This cell volume increase promoted TRPV4 activation in the form of TRPV4-mediated currents (middle and right panels). Modified from (32) with permission.

Figure 4

The N-terminus of TRPV4 dictates the directionality of the volume sensing. Channel structures of TRPV4 (top), TRPV4:TRPV1 (VR.5'sv) chimera (with the TRPV4 N terminus replaced by that of VR.5’sv, middle) and VR.5’sv (bottom). The constructs were co-expressed with AQP4 in Xenopus laevis oocytes, which were exposed to a hyposmotic or hyperosmotic gradient (Δ100 mOsm) leading to robust cell swelling or cell shrinkage (volume trace, top). TRPV4 responded with augmented membrane currents to a cell volume increase unless its N-terminus was replaced by that of the shrinkage-sensitive VR.5’sv variant of TRPV1 (middle and right panels). Modified from (33).

Figure 5

The TRPV4 N- and C-termini contain an abundance of consensus sites for protein kinases. Modified from (65) with permission.

Figure 6

A schematic depicting the mechanisms underlying swelling-induced TRPV4 activation. Increased cell volume activates TRPV4 irrespective of the molecular mechanism underlying the cell swelling. The TRPV4-mediated response to cell volume changes is dictated by its distal-most part of the N terminus, with cell-specific requirement for PLA₂ activity as permissive for swelling-induced activation of TRPV4.