ASIC3-dependent spinal cord nociceptive signaling in cutaneous pain induced by lysophosphatidyl-choline

ABSTRACTLysophosphatidyl-choline (LPC), a member of the phospholipid family, has recently emerged as an interesting new player in pain. It has been proposed to mediate pain through Acid-Sensing Ion Channel 3 (ASIC3), a pain-related channel mainly expressed in peripheral sensory neurons. LPC potentiates ASIC3 current evoked by mild acidifications, but can also activate the channel at physiological pH, and its local injection in rodents evokes ASIC3-dependent pain. We combine here in vivo recordings of spinal cord neuron activity with subcutaneous LPC injection to analyze the mechanism of action associated with the LPC-induced, ASIC3-dependent pain in peripheral and spinal cord neurons. We show that a single cutaneous injection of LPC exclusively affects the nociceptive pathway. It evokes an ASIC3-dependent short-term sensitization of nociceptive fibers that drives hyperexcitability of projecting neurons within the dorsal spinal cord without apparent central sensitization.

Lysophosphatidyl choline modulates mechanosensitive L-type Ca2+ current in circular smooth muscle cells from human jejunum

The L-type Ca2+ channel expressed in gastrointestinal smooth muscle is mechanosensitive. Direct membrane stretch and shear stress result in increased Ca2+ entry into the cell. The mechanism for mechanosensitivity is not known, and mechanosensitivity is not dependent on an intact cytoskeleton. The aim of this study was to determine whether L-type Ca2+ channel mechanosensitivity is dependent on tension in the lipid bilayer in human jejunal circular layer myocytes. Whole cell currents were recorded in the amphotericin-perforated-patch configuration, and lysophosphatidyl choline (LPC), lysophosphatidic acid (LPA), and choline were used to alter differentially the tension in the lipid bilayer. Shear stress (perfusion at 10 ml/min) was used to mechanostimulate L-type Ca2+ channels. The increase in L-type Ca2+ current induced by shear stress was greater in the presence of LPC (large head-to-tail proportions), but not LPA or choline, than in the control perfusion. The increased peak Ca2+ current also did not return to baseline levels as in control conditions. Furthermore, steady-state inactivation kinetics were altered in the presence of LPC, leading to a change in window current. These findings suggest that changes in tension in the plasmalemmal membrane can be transmitted to the mechanosensitive L-type Ca2+ channel, leading to altered activity and Ca2+ entry in the human jejunal circular layer myocyte.