Various ion channels are subject to open channel block (OCB) by divalent cations, in which a blocking ion binds to the inside of the channel. For instance, ligand binding alone is insufficient to enable traversal of the ligand-gated N-methyl-D-aspartate (NMDA) channel by nonblocking ions; membrane depolarization—leading to the expulsion of a blocking Mg2+—is also required. The Drosophila transient receptor potential (TRP) and TRP-like (TRPL) channels are subject to OCB; however, puzzlingly, these channels mediate light-induced current in the absence of previous membrane depolarization. Lipids are known to activate these channels and, using whole-cell patch-clamp analysis of TRPL and TRP channels in Drosophila photoreceptor cells or TRPL channels heterologously expressed in S2 cells, Parnas et al. showed that exposure to linoleic acid (LA) relieved OCB. Light activates TRPL and TRP in Drosophila photoreceptor cells by way of phospholipase C (PLC); experiments using a fluorescent reporter that translocates from the membrane in response to PLC hydrolysis of phosphatidylinositol 4,5-bisphosphate (PIP2) indicated that the effects of LA were independent of PLC activation, as did experiments in PLC-deficient photoreceptor cells. However, like LA, PLC activation relieved OCB. LA appeared to reduce the efficiency of blocking cations by increasing the rate with which they crossed the channel. Analysis of OCB under various conditions calculated to affect membrane properties (hypoosmotic solutions, exposure of the intracellular membrane to polylysine to sequester PIP2, and exposure to a toxin that affects the channel-lipid interface) indicated that LA relieved OCB by affecting membrane properties and thereby membrane lipid-channel interactions. Intriguingly, LA also removed OCB from NMDA channels without depolarization. The authors thus propose that relief of OCB through lipid-producing pathways provides a previously unappreciated mechanism for modulating ion channel activity.
M. Parnas, B. Katz, S. Lev, V. Tzarfaty, D. Dadon, A. Gordon-Shaag, H. Metzner, R. Yaka, B. Minke, Membrane lipid modulations remove divalent open channel block from TRP-like and NMDA channels. J. Neurosci. 29, 2371–2383 (2009). [Abstract] [Full Text]