Cell membrane Gramicidin

This review addresses the issues of the chemical and physical processes whereby inorganic anions and cations are selectively retained by or passed through cell membranes. The channel and carrier mechanisms of membranes permeation are treated by means of model systems. The models are the planar lipid bilayer for the cell membrane, Gramicidin for the channel mechanism, and Valinomycin for the carrier mechanism. 

Left and center Two gramicidin A molecules associate to span a cell membrane. Right Axial view showing ion channel. [Structure from B. Roux, "Computational Studies of the Gramicidin Channel." Acc. Chem. Res. 2002,35,366. based on solid-state nuclear magnetic resonance. Schematic at left from L. Stryer. Biochemistry,... 

Metal cations dissolve in water and are said to be hydrophilic ( water loving ). Cell membranes exclude water and are described as hydrophobic ( water hating ). Gramicidin A lodges in the cell membrane because the outside of the molecule is hydrophobic. Na+ and K+ pass through each hydrophilic pore at a rate of 107 ions/s. The pore is selective for monovalent cations it excludes anions and more highly charged cations. 

A parallel development came from studies on artificial lipid bilayer membranes. Hladky and Hay don (1984) found that when very small amounts of the antibiotic gramicidin were introduced into such a membrane, its conductance to electrical current flow fluctuated in a stepwise fashion. It looked as though each gramicidin molecule contained an aqueous pore that would permit the flow of monovalent cations through it. Could the ion channels of natural cell membranes act in a similar way To answer this question, it was first necessary to solve the difficult technical problem of how to record the tiny currents that must pass through single channels. 

There are many examples of peptides that cannot form transmembrane channels on their own but can do so through aggregation. The gramicidin antibiotics, produced by bacteria as part of their chemical defence system, are only 1.6 nm or so in length [11], Specific placement of side chains, such as four tryptophan residues towards the C-terminus, ensures that the helix penetrates cell membranes to a particular depth but does not pass through the membrane. 

Like polymyxin B, gramicidin changes permeability characteristics of the cell membrane, thus killing the cell. However, in contrast to polymyxin B, gramicidin is effective against gram-positive bacteria. It replaces bacitracin in some fixed-combination antibacterial solutions used topically for ocular infections (see Table 11-6). 

Gramicidin act-s as an ionophore in bacterial cell membranes to cause the los-s of potassium ion from the cell. It is baetericidal. 

The antibiotics valinomycin and gramicidin A operate by acting, within the cell membrane as ion carriers and ion channels respectively (see Chapter 10). 

The peptides valinomycin (Fig. 10.64) and gramicidin A (Fig. 10.67) both act as ion conducting antibiotics and allow the uncontrolled movement of ions across the cell membrane. Unfortunately, both these agents show no selective toxicity for bacterial over mammalian cells and are therefore useless as therapeutic agents. Their mechanism of action is interesting nevertheless. 

A group of antibiotics (e.g., valinomycin, nigericin, and gramicidin A) transport cations across the cell membrane. Such agents, known as ionophores, are widely used to probe membrane structure and function. Ionophores uncouple oxidative phosphorylation. Valinomycin, a cyclic peptide (Figure 14-17), forms a lipid-soluble complex with K+ that readily passes through the inner membrane, whereas K+ by itself does not. In the valinomycin-K complex, hydrophobic groups, present on the outside, facilitate transport of the complex in the lipid environment ... 

Whole-cell mode— perforated. This mode is similar to the conventional whole-cell mode but the cell membrane is not ruptured. Instead, small amounts of an ionophore, such as amphotericin B, nystatin, or gramicidin, are added into the electrode solution, which produce very small perforations in the membrane patch surrounded by the electrode. Only small ions (K, Na" ") and not larger ones (Ca ) or any other molecules can move freely through the formed membrane holes. This mode allows ion current recordings while the internal content of the cell is kept intact. 

In their similar action on the cell membrane the tyrocidines, gramicidins and the polymyxins resemble other surface active agents. Like these, they contain also lipophilic and lipophobic groups, which, as has been revealed by studies on gramicidins, may be separated in the molecule by being fixed on different sides of the molecular plane. 

There are several antibiotics called ionophores. Some notable examples are monensin, nonactin, gramicidin, and valinomycin. The structures of monensin and nonactin are shown below, lonophore antibiotics like monensin and nonactin coordinate with metal cations in a manner similar to crown ethers. Their mode of action has to do with disrupting the natural gradient of ions on each side of the cell membrane. 

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