Connexin channels and phospholipids: association and modulation

<p>Abstract</p> <p>Background</p> <p>For membrane proteins, lipids provide a structural framework and means to modulate function. Paired connexin hemichannels form the intercellular channels that compose gap junction plaques while unpaired hemichannels have regulated functions in non-junctional plasma membrane. The importance of interactions between connexin channels and phospholipids is poorly understood.</p> <p>Results</p> <p>Endogenous phospholipids most tightly associated with purified connexin26 or connexin32 hemichannels or with junctional plaques in cell membranes, those likely to have structural and/or modulatory effects, were identified by tandem electrospray ionization-mass spectrometry using class-specific interpretative methods. Phospholipids were characterized by headgroup class, charge, glycerol-alkyl chain linkage and by acyl chain length and saturation. The results indicate that specific endogenous phospholipids are uniquely associated with either connexin26 or connexin32 channels, and some phospholipids are associated with both. Functional effects of the major phospholipid classes on connexin channel activity were assessed by molecular permeability of hemichannels reconstituted into liposomes. Changes to phospholipid composition(s) of the liposome membrane altered the activity of connexin channels in a manner reflecting changes to the surface charge/potential of the membrane and, secondarily, to cholesterol content. Together, the data show that connexin26 and connexin32 channels have a preference for tight association with unique anionic phospholipids, and that these, independent of headgroup, have a positive effect on the activity of both connexin26 and connexin32 channels. Additionally, the data suggest that the likely in vivo phospholipid modulators of connexin channel structure-function that are connexin isoform-specific are found in the cytoplasmic leaflet. A modulatory role for phospholipids that promote negative curvature is also inferred.</p> <p>Conclusion</p> <p>This study is the first to identify (endogenous) phospholipids that tightly associate with connexin channels. The finding that specific phospholipids are associated with different connexin isoforms suggests connexin-specific regulatory and/or structural interactions with lipid membranes. The results are interpreted in light of connexin channel function and cell biology, as informed by current knowledge of lipid-protein interactions and membrane biophysics. The intimate involvement of distinct phospholipids with different connexins contributes to channel structure and/or function, as well as plaque integrity, and to modulation of connexin channels by lipophilic agents.</p

Polyethylene glycols interact with membrane glycerophospholipids: is this part of their mechanism for hypothermic graft protection?

Polyethylene glycol (PEG), a high-molecular-weight colloid present in new organ preservation solutions, protects against cold ischemia injuries leading to better graft function of transplanted organs. This protective effect cannot be totally explained by immuno-camouflaging property or signaling-pathway modifications. Therefore, we sought for an alternative mechanism dependent on membrane fluidity. Using the Langmuir–Pockles technique, we show here that PEGs interacted with lipid monolayers of defined composition or constituted by a renal cell lipid extract. High-molecular-weight PEGs stabilized the lipid monolayer at low surface pressure. Paradoxically, at high surface pressure, PEGs destabilized the monolayers. Hypothermia reduced the destabilization of saturated monolayer whereas unsaturated monolayer remained unaffected. Modification of ionic strength and pH induced a stronger stabilizing effect of PEG 35,000 Da which could explain its reported higher effectiveness on cold-induced injuries during organ transplantation. This study sheds a new light on PEG protective effects during organ preservation different from all classical hypotheses

Targeted pharmaceutical nanocarriers for cancer therapy and imaging

The use of various pharmaceutical nanocarriers has become one of the most important areas of nanomedicine. Ideally, such carriers should be specifically delivered (targeted) to the pathological area to provide the maximum therapeutic efficacy. Among the many potential targets for such nanocarriers, tumors have been most often investigated. This review attempts to summarize currently available information regarding targeted pharmaceutical nanocarriers for cancer therapy and imaging. Certain issues related to some popular pharmaceutical nanocarriers, such as liposomes and polymeric micelles, are addressed, as are different ways to target tumors via specific ligands and via the stimuli sensitivity of the carriers. The importance of intracellular targeting of drug- and DNA-loaded pharmaceutical nanocarriers is specifically discussed, including intracellular delivery with cell-penetrating peptides