SK3 channels are abnormaly expressed in metastatic cells, and
Ohmline (OHM), an
ether lipid, has been shown to reduce the activity of SK3 channels and the migration capacity of
cancer cells. OHM incorporation into the plasma membrane is proposed to dissociate the
protein complex formed between SK3 and Orai1, a
potassium and a
calcium channel, respectively, and would lead to a modification in the
lipid environment of both the
proteins. Here, we report the synthesis of deuterated OHM that affords the determination, through solid-state NMR, of its entire partitioning into membranes mimicking the SK3 environment. Use of deuterated
lipids affords the demonstration of an OHM-induced membrane disordering, which is dose-dependent and increases with increasing amounts of
cholesterol (CHOL). Molecular dynamics simulations comfort the disordering action and show that OHM interacts with the carbonyl and
phosphate groups of stearoylphosphatidylcholine and
sphingomyelin and to a minor extent with CHOL. OHM is thus proposed to remove the CHOL
OH moieties away from their main binding sites, forcing a new rearrangement with other
lipid groups. Such an interaction takes its origin at the
lipid-water interface, but it propagates toward the entire
lipid molecules and leads to a cooperative destabilization of the
lipid acyl chains, that is, membrane disordering. The consequences of this reorganization of the
lipid phases are discussed in the context of the OHM-induced inhibition of SK3 channels.