Singular Interaction between an Antimetastatic Agent and the Lipid Bilayer: The Ohmline Case

Abstract

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.

C-Glucosylation as a tool for the prevention of PAINS-induced membrane dipole potential alterations

“…This superficial positioning in the membrane may further lead to a remodelling effect through the rearrangement of existing hydrogen-bond networks between phospholipid headgroups and surface water molecules, which mediate membrane hydration mechanisms. In cholesterol-containing and more complex lipid systems, these interactions may even block the binding sites of the hydroxy group of cholesterol in phospholipids and sphingolipids 62 leading to alterations in membrane thickness and fluidity 63 . In accordance, quercetin–a paradigmatic example of polyphenols with diverse and even promiscuous bioactivities–was recently shown to increase membrane hydration by interfering with cholesterol/sphingolipid-enriched domains, and is, like resveratrol, more superficially located in complex lipid mixtures 64 .…”

“…Indeed, POPC headgroups are endowed with a single large electric dipole inherent to a nitrogen-centered positive charge, which is, therefore, evenly oriented. This leads to a water-structuring effect that creates hydration-associated repulsion forces in the membrane 63 . In contrast, glycolipid membranes are able to counter-act such effects through the remodelling of hydrogen bonding patterns that modulate membrane surface hydration mechanisms, namely through lipid-lipid, lipid-water and water-water interactions.…”

Roles of endogenous ether lipids and associated PUFAs in the regulation of ion channels and their relevance for disease

“…The SK3 channel is sensitive to cholesterol content and membrane state (34). In fact, we reported the effect of 1-O-hexadecyl-2-O-methyl-sn-glycero-3-lactose (Ohmline), a synthetic EL, which inhibits SK3 channel activity by removing the cholesterol OH moieties away from their main binding sites, including the SK3 channel (3). This study suggests that ELs can modulate the lipid environment of ion channels and therefore regulate their activities.…”

Molecular Choreography and Structure of Ca2+ Release-Activated Ca2+ (CRAC) and KCa2+ Channels and Their Relevance in Disease with Special Focus on Cancer

“…Mechanistically, it has been reported that ohmline interferes with the order of lipid bilayers rich in cholesterol. Whether there is a direct interaction between ion channels and these ether lipids is currently unknown [ 322 ]. Nevertheless, it has recently been reported that SK3 possesses a PIP 2 -binding site making a specific interaction of SK3 and such lipid-synthetic alkaloids likely [ 39 ].…”