The ion channel TRPV4 acts as a thermosensor when interacts with membrane lipids
We detect rapid changes in temperature within a wide range, allowing us to sense from cold snow to sun heating at the beach. TRP ion channels are behind the molecular identity of the proteins that confer thermosensation. One of these channels, TRPV4, detects temperature in the physiological range (27-40ºC) but it was not known whether the channel is a true thermosensor or a downstream effector of a yet unknown body temperature sensor.
A research study, led by the Molecular Physiology and Channelopathies Laboratory of the UPF Department of Experimental and Health Sciences, has unravelled the basic mechanism of TRPV4 activation by warm temperature. The study in which researchers from Harvard University also collaborated, has been published on 20 May in the Proceedings of the National Academy of Sciences (PNAS). The UPF researchers of this scientific article are Anna Garcia-Elias, Sanela Mrkonjic, Carlos Pardo, Cristina Plata, Fanny Rubio-Moscardo, Rubén Vicente and Miguel A. Valverde.
TRPV4 is a non-selective cation channel that responds to osmotic, mechanical and temperature stimulation, thereby contributing to many different physiological functions: cellular and systemic volume homeostasis, vasodilation, nociception, bladder voiding, ciliary beat frequency regulation and skeletal regulation. Osmotic and mechanical sensitivity of TRPV4 depends on the generation of intracellular signalling messengers, while the mechanism leading to temperature-mediated activation it was not known.
The research team has combined numerous approaches to evaluate TRPV4 channel activity in response to temperature and osmotic stimuli: electrophysiological and calcium imaging, techniques that allow depletion of the phosphatidylinositol-4,5-biphosphate (PIP 2) lipid from the plasma membrane, site-directed mutagenesis of the channel protein and FRET-based intermolecular interaction of TRPV4 subunits labeled with fluorescent proteins.
The study concludes that TRPV4 requires the interaction of PIP 2 with a stretch of positive charges at the N-tail of the channel protein in order to be activated by hypotonicity and heat. Conditions that break down PIP 2, for example, following the activation of G-protein coupled receptors, preclude the activation of TRPV4.
The study provides the first piece of structural evidence suggesting that PIP 2 interaction with the channel brings the cytosolic tails closer to the plasma membrane, generating a more distended cytosolic region that facilitates the opening of the channel gate and the crossing of ions in response to heat and hypotonic cell swelling.
Reference study: Phosphatidylinositol-4,5-biphosphate-dependent rearrangement of TRPV4 cytosolic tails enables channel activation by physiological stimuli. Anna Garcia-Elias, Sanela Mrkonjić, Carlos Pardo-Pastor, Hitoshi Inada, Ute A. Hellmich, Fanny Rubio-Moscardó, Cristina Plata, Rachelle Gaudet, Rubén Vicente and Miguel A. Valverde. PNAS. doi: 10.1073/pnas.1220231110 . 20/5/2013.