TRAAK is an ion channel from the two-pore domain potassium (K2P) channel family with roles in maintaining the resting membrane potential and fast action potential conduction. TRAAK (K2P4.1) and other K2P channels are gated by a wide range of physical and chemical stimuli, such as phospholipids. In fact, an intramembrane opening between subunits of TRAAK is penetrated by a lipid acyl chain of unknown identity with a proposed role in mechanosenstation. More generally, the affinity and selectivity of K2P4.1 towards lipids remains poorly understood. Here we show the two isoforms of K2P4.1 have distinct binding preferences for lipids. Binding affinity is dependent on acyl chain length and position within the glycerophospholipid. Unexpectedly, the channel can also discriminate the fatty acid linkage at the sn-1 position resulting in a reduced binding affinity for vinyl ether and ether containing lipids, plasmalogen ethanolamine and platelet activating factor, respectively. Of the 33 lipids interrogated using native mass spectrometry, phosphatidic acid (PA) had the lowest equilibrium dissociation constants for both isoforms of K2P4.1. Liposome potassium flux assays with K2P4.1 reconstituted in defined lipid environments show that those containing PA activate the channel in a dose-dependent fashion. These findings draw a relationship between the strength of individual lipid binding events to K2P4.1 and the channel’s activity. Our results begin to define the molecular requirements for the specific binding of lipids to K2P4.1.

Selective regulation of human TRAAK channels by phospholipids

ACS Spring Meeting 2021

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