Ion channels, in biological membranes

When supramolecular polymers are treated with bulky stopper groups, they may form poly[2]rotaxane daisy chains [32,60-68]. Cyclic tri[2]rotaxanes (daisy chain necklace) containing cyclodextrins have been prepared from the mixture of 6-(4-aminocinnamoyl)-Q -CD and 2,4,6-trinitrobenzene sulfonic acid sodium salt [50,59] in an agueous solution (Fig. 21). If the molecule changes its conformation (or co-conformation), the ring may expand or shrink by external conditions (temperature, solvents, photochemically, elec-trochemically). These compounds are important because the cycle can be used as a chemical valve as seen in ion channels in biological membranes. 

Evidence for ion channels in biological membranes was introduced in the 1970s. Possibly the most significant experiment was by Neher and Sakmann, who recorded single ion channel currents in muscle fibers. Many types of channels for sodium, potassium, calcium, and chloride ions have been described, and... 

Significant deviations from Hooge s formula also were found for ion channels in biological membranes after special difference procedures (7) for recording fluctuations from specific channels were introduced. For example, for sodium channels modified by batrachotoxin in myelinated nerve (62), the number of mobile ions derived from the formula with the original value of a is nearly 30 times higher than the number of open-membrane channels. 

The topic of ion transfer free energy across the liquid/liquid interface is closely related to the problem of ion channels in biological membranes, but this is outside the scope of this chapter. 

Martinac B. Mechanosensitive channels. In Biological Membrane Ion Channels Dynamics, Structure, and Apphcations. Chung SH, Andersen OS, Krishnamurthy V, eds. 2007. Springer, New York, pp. 369-398. 

After Chapter 1 on non-mediated transport of lipophilic compounds. Chapters 2 and 3 are devoted to the passive transport of water and other small polar molecules and to that of ions. Chapter 4 discusses the insertion of ionophores in lipid bilayers as model systems for carriers and channels in biological membranes. Chapter 5 treats the general principles of mediated transport. Chapters 6, 7 and 8 are devoted to the ATPases, which are involved in the primary active transport of Na, Ca and H, respectively. After Chapters 9 and 10 on specific transport systems in mitochondria and bacteria, the book concludes with Chapters 11 and 12 on secondary active transport, the coupling of the transport of metabolites and water to that of ions. 

In a different context, a micropipette has been applied to monitor the current through a single-ion channel in a biological membrane. The patch-clamp technique invented by Sackmann and Neher [119] led to their Nobel Prize in medicine. The variations in channel current with voltage, concentration, type of ions, and type of channels have been explored. While the functions of specific channels, in particular their ionic selectivity, have been well known, only a handful of channels have the internal geometry and charge distribution determined. The development of a theory to interpret the mass of channel data and to predict channel action is still lacking. 

It has been known for some years that gramicidin forms transmembrane ion channels in lipid bilayers and biological membranes and that these channels are assembled from two molecules of the polypeptide 213). The channels are permeable specifically to small monovalent cations [such as H+, Na+, K+, Rb+, Cs+, Tl+, NH4+, CHjNHj, but not (CH3)2NH2+J and small neutral molecules (such as water, but not urea). They do not allow passage of anions or multivalent cations 21 n. 

The conformation of gramicidin in aqueous solution has been extensively studied. A lipophilic left-handed helical structure has been proposed for gramicidin A 0 1 1. it was proposed that the mode of action of gramicidin is due to the formation of ion transport channels across biological membranes. 

In this chapter we first describe the composition of cellular membranes and their chemical architecture— the molecular structures that underlie their biological functions. Next, we consider the remarkable dynamic features of membranes, in which lipids and proteins move relative to each other. Cell adhesion, endocytosis, and the membrane fusion accompanying neurotransmitter secretion illustrate the dynamic role of membrane proteins. We then turn to the protein-mediated passage of solutes across membranes via transporters and ion channels. In later chapters we discuss the role of membranes in signal transduction (Chapters 12 and 23), energy transduction (Chapter 19), lipid synthesis (Chapter 21), and protein synthesis (Chapter 27). 

We have already seen in Section 2.2 how the transport of both anions and cations is a vital part of biochemistry. We will examine supramolecular models of biological ion channels in detail in Chapter 12 but here we focus on some simple ion transport systems (ionophores) relevant to simultaneous anion and cation binding. Because of the need to maintain overall and local charge neutrality during any transport process the transport of individual ions across a biological or artificial membrane never occurs in isolation. There are two kinds of primary transport processes. Ion exchange or antiport, occurs when chemically different ions of like charge such as Na+ and K+ are simultaneously transported in... 

Fig. B.6.1. Schematic representation of the action of gramicidin A (a), an ionophore (b), and a ligand-controlled ion channel (c) in the transport of ions across a biological membrane.

Standard molecular mechanics (MM) force fields have been developed that provide a good description of protein structure and dynamics,21 but they cannot be used to model chemical reactions. Molecular dynamics simulations are very important in simulations of protein folding and unfolding,22 an area in which they complement experiments and aid in interpretation of experimental data.23 Molecular dynamics simulations are also important in drug design applications,24 and particularly in studies of protein conformational changes,25,26 simulations of the structure and function of ion channels and other membrane proteins,27-29 and in studies of biological macromolecular assemblies such as F-l-ATPase.30... 

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