Lipid raft disruption inhibits the activation of Transient Receptor Potential Vanilloid 1, but not TRP Melastatin 3 and the voltage-gated L-type calcium channels in sensory neurons

Transient Receptor Potential (TRP) ion channels like Vanilloid 1 (TRPV1) and Melastatin 3 (TRPM3) are nonselective cation channels expressed in primary sensory neurons and peripheral nerve endings, which are located in cholesterol- and sphingolipid-rich membrane lipid raft regions and have important roles in pain processing. Besides TRP ion channels a wide variety of voltage-gated ion channels were also described in the membrane raft regions of neuronal cells. Here we investigated the effects of lipid raft disruption by methyl-beta-cyclodextrin (MCD) and sphingomyelinase (SMase) on TRPV1, TRPM3 and voltage-gated L-type Ca²⁺ channel activation in cultured trigeminal neurons and sensory nerve terminals of the trachea. We also examined the mechanism of action of MCD by <i>in silico</i> modeling. Disruption of lipid rafts by MCD or SMase did not alter CIM0216-induced TRPM3 cation channel activation and the voltage-gated L-type Ca²⁺ channel activation by FPL 64126 or veratridine neither on trigeminal sensory neurons nor sensory nerve terminals. We provided the first structural explanation with <i>in silico</i> modeling that the activation of TRPV1, TRPM3 and voltage-gated L-type Ca²⁺ channels is affected differently by the cholesterol content surrounding them in the plasma membrane. It is concluded that modifying the hydrophobic interactions between lipid rafts and ion channels might provide a selective novel mechanism for peripheral analgesia.