Ca2+-independent Phospholipase A2-dependent Gating of TRPM8 by Lysophospholipids

Abstract

TRPM8 represents an ion channel activated by cold temperatures and cooling agents, such as menthol, that underlies the cold-induced excitation of sensory neurons. Interestingly, the only human tissue outside the peripheral nervous system, in which the expression of TRPM8 transcripts has been detected at high levels, is the prostate, a tissue not exposed to any essential temperature variations. Here we show that the TRPM8 cloned from human prostate and heterologously expressed in HEK-293 cells is regulated by the Ca 2؉ -independent phospholipase A 2 (iPLA 2 ) signaling pathway with its end products, lysophospholipids (LPLs), acting as its endogenous ligands. LPLs induce prominent prolongation of TRPM8 channel openings that are hardly detectable with other stimuli (e.g. cold, menthol, and depolarization) and that account for more than 90% of the total channel open time. Down-regulation of iPLA 2 resulted in a strong inhibition of TRPM8-mediated functional responses and abolished channel activation. The action of LPLs on TRPM8 channels involved either changes in the local lipid bilayer tension or interaction with the critical determinant(s) in the transmembrane channel core. Based on this, we propose a novel concept of TRPM8 regulation with the involvement of iPLA 2 stimulation. This mechanism employs chemical rather than physical (temperature change) signaling and thus may be the main regulator of TRPM8 activation in organs not exposed to any essential temperature variations, as in the prostate gland.Although TRPM8, a member of the transient receptor potential (TRP) 6 channel family, was originally cloned from the prostate (1), recent studies have firmly established its function as a cold/menthol receptor in sensory neurons (2, 3). Thus, an outstanding problem heightened by a significant TRPM8 up-regulation in several tumors (prostate, lung, breasts, skin) concerns the whole spectrum of the physiological and pathophysiological roles of TRPM8 in those tissues devoid of any significant temperature variations. Revealing possible alternative molecular events leading to TRPM8 activation at constant temperature would undoubtedly help to uncover other TRPM8 functions beyond the cold sensation.Recently, a model ascribing TRPM8 activation to cold/menthol-induced shifts in the channel voltage dependence toward physiological membrane potentials has been proposed (4). Although attractive in its explanation of the temperature sensitivity, this model seems to be insufficient to account for TRPM8 activation in those tissues that are not exposed to any essential temperature variations, such as prostate. Moreover, prominent rundown of TRPM8 activity in excised patches (4, 5) raised a possibility that some endogenous ligands might be necessary for channel activation. Phosphatidylinositol 4,5-bisphosphate (PIP 2 ) has recently been found to be such a factor, since it was capable not only of restoring menthol-activated TRPM8 current after its rundown in excised patches but also of activating the current independently of menthol (5, 6...

Transient receptor potential melastatin 8 channel involvement in the regulation of vascular tone

“…Similar observations of menthol effects in other smooth muscle tissues have been made previously [guinea-pig ileum (12), guinea-pig bronchus (39), and guinea-pig trachea (14)]. Notably, several studies (1,6,34,41) have shown that the channel can be expressed both on plasma membrane and endoplasmic reticulum and can alter intracellular calcium (Ca 2ϩ ) fluxes through both routes. Its localization on the perimeter of the VSM cell and deeper in the cytosol is also consistent with such dual roles (Fig.…”

“…2C). TRPM8 localized in the sarcoplasmic reticulum membrane can support cold/menthol/icilin-induced Ca 2ϩ release from the sarcoplasmic reticulum causing Ca 2ϩ store depletion (1,34). This seems to be one of the most likely mechanisms that can explain vasoconstrictor inhibition by TRPM8 agonists, but further studies are required to substantiate this view.…”

“…Addressing the apparently paradoxical expression of TRPM8 in tissues not exposed to any essential temperature variations, we have recently characterized a novel biochemical pathway for TRPM8 activation. This involves multiple cascades of Ca 2ϩ store depletion, Ca 2ϩ -independent phospho-lipase A 2 (iPLA 2 ) activation, and synthesis of lysophospholipids that can activate TRPM8 at physiological temperature (1).…”

Pannexin-1-Mediated Intracellular Delivery of Muramyl Dipeptide Induces Caspase-1 Activation via Cryopyrin/NLRP3 Independently of Nod2

“…Together, these studies support a model whereby ATP stimulation via P2X 7 R leads to the formation of a functional pore through pannexin-1 that allows the passage of certain molecules, such as MDP, to the cytosol triggering caspase-1 activation. Because pannexin-1 is a transmembrane protein located at the cell surface and the endoplasmic reticulum (42,43), it is likely that pannexin-1 acts at the membrane of acidified vacuolar structures, such as lysosomes, to regulate MDP release into the cytosol. It is also formally possible that pannexin-1 controls the passage of MDP from acidified vesicles to the cytosol by an indirect mechanism.…”

Inorganic Polyphosphate Modulates TRPM8 Channels

“…TRPM8 is activated by low temperatures in the range of 8-26uC and a number of chemical compounds such as menthol, icilin, eucalyptol, geraniol and linalool [4,5,6]. Several other factors, such as voltage [7,8], pH [8], lysophospholipids and fatty acids [9,10] also modulate TRPM8 activity.…”