Disruption of palmitate-mediated localization; a shared pathway of force and anesthetic activation of TREK-1 channels.

TWIK related K+ channel (TREK-1) is a mechano- and anesthetic sensitive channel that when activated attenuates pain and causes anesthesia. Recently the enzyme phospholipase D2 (PLD2) was shown to bind to the channel and generate a local high concentration of phosphatidic acid (PA), an anionic signaling lipid that gates TREK-1. In a biological membrane, the cell harnesses lipid heterogeneity (lipid compartments) to control gating of TREK-1 using palmitate-mediated localization of PLD2. Here we discuss the ability of mechanical force and anesthetics to disrupt palmitate-mediated localization of PLD2 giving rise to TREK-1's mechano- and anesthetic-sensitive properties. The likely consequences of this indirect lipid-based mechanism of activation are discussed in terms of a putative model for excitatory and inhibitory mechano-effectors and anesthetic sensitive ion channels in a biological context. Lastly, we discuss the ability of locally generated PA to reach mM concentrations near TREK-1 and the biophysics of localized signaling. Palmitate-mediated localization of PLD2 emerges as a central control mechanism of TREK-1 responding to mechanical force and anesthetic action. This article is part of a Special Issue entitled: Molecular biophysics of membranes and membrane proteins.