Ion Channels In Bilayer Membranes Research Articles

Synthetic Ion Channels in Bilayer Membranes

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Synthetic ion channels in bilayer membranes

Natural ion channels are large protein complexes that regulate key functions of cells. Supramolecular chemists have been able to take hints from Nature to design and prepare completely synthetic ion channel systems that reproduce many of the fundamental functions of natural channels. This tutorial review introduces the field to non-specialists. It examines the design, synthesis, incorporation, and characterization of synthetic ion channels in bilayer membranes, and points to potential applications of synthetic ion channels.

Mutant Huntington Protein Forms Channels in Lipid Membranes

Huntington’s Disease (HD) is a hereditary neurodegenerative disorder characterized by motor, psychiatric, and cognitive symptoms. HD is caused by polyglutamine repeat expansion in the first exon of the huntingtin (Htt) protein. Extended tracts of polyglutamine (PG) have been implicated in the pathogenicity of the mutant protein Htt and have been shown to form ion channels in planar lipid bilayer membranes (BLM). We report here that a Htt mutant protein comprising the first exon of Htt with a 46 residue PG repeat can induce large long-lived ion channels in BLM. Channel formation is enhanced at acidic pH. A comparable mutant containing a 25 residue PG repeat does not form channels. These lines of evidence suggest that Htt and other PG mutant proteins may damage cells via a channel forming mechanism, that could cause damage to the plasma membrane by running down ionic gradients discharging membrane potential, allowing influx of toxic ions such as Ca(2+). Htt may damage intracellular membranes such as the lysomal or the mitochondrial membrane via leakage of toxic enzymes or triggering of apoptosis. We propose that channel formation by Htt may be a mechanism of cellular toxicity as well established for microbial toxins and the existence of at least six other “amyloid” channels relevant to diseases such as Alzheimer’s and Creutzfeld-Jakob, suggests that this may be a widespread pathogenic mechanism. Supported by Alzheimer Association 441587-DS-58580

Ion channel formation from a calix[4]arene amide that binds HCl.

The ion transport activity of calix[4]arene tetrabutylamide 1,3-alt 2 was studied in liposomes, planar lipid bilayers, and HEK-293 cells. These experiments, when considered together with (1)H NMR and X-ray crystallography data, indicate that calix[4]arene tetrabutylamide 2 (1) forms ion channels in bilayer membranes, (2) mediates ion transport across cell membranes at positive holding potential, (3) alters the pH inside liposomes experiencing a Cl(-) gradient, and (4) shows a significant Cl(-)/SO(4)(2)(-) transport selectivity. An analogue, calix[4]arene tetramethylamide 1, self-assembles in the presence of HCl to generate solid-state structures with chloride-filled and water-filled channels. Structureminus signactivity studies indicate that the hydrophobicity, amide substitution, and macrocyclic framework of the calixarene are essential for HCl binding and transport. Calix[4]arene tetrabutylamide 2 is a rare example of an anion-dependent, synthetic ion channel.