Transmembrane ion channels

The article concludes by examining recent research involving transmembrane ion channels particularly those molecular aggregates and macromolecular systems where helicity is involved in construction of the channel. 

Many of these materials form voltage-gated transmembrane ion channels, i.e. they exhibit non-linear current voltage curves, unlike the polyene antibiotics and gramicidin A which have linear current voltage curves. Of the peptaibol antibiotics the most thoroughly investigated substance to date is alamethicin 201 203>. 

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. 

Langs, D. A. (1988). Three-dimensional structure at 0.86 A of the uncomplexed form of the transmembrane ion channel peptide gramicidin A. Science 241, 188-191. 

Arseniev, A. S., Barsukov, I. L., Bystrov, V. F., Lomize, A. L. and Ovchinnikov, Y. A. (1985). 1H-NMR study of gramicidin-A transmembrane ion channel head-to-head right handed single stranded helices, FEBS Lett., 186, 168-174. 

Ghadiri MR, Granja JR, Buehler LK. Artificial transmembrane ion channels from selfassembling peptide nanotubes. Nature (Lond) 1994 369 301-304. 

Classes I, III, and IV all involve transmembrane ion channels Classes I and III involve Na+ channels. Class I compounds are designed to block cardiac Na channels in a voltage-dependent manner, similar to local anesthetics. Not surprisingly, many of these Class I agents are either local anesthetics or are structurally based on local anesthetics. Class I compounds include procainamide (7.15), disopyramide (7.16), amiodarone (7.17), lido-caine (7.5), tocainide (7.18), mexiletine (7.19), and flecainide (7.20). The majority of these compounds possess two or three of the fundamental structural building blocks found within local anesthetics. Propranolol (7.21) is the prototypic Class II agent. Class III compounds include molecules that block outward K channels, such as sotalol (7.22) and dofetilide (7.23), and molecules that enhance an inward Na current, such as... 

Figure 24. A plausible mechanism for the formation of voltage-dependent ion channels. Trapezoidal cylinders symbolize the transmembrane ion channel composed of assembles of uneven (cases a and b) or even (case c) aggregation number of the net negative ion pair 2, which is symbolized by at both surfaces of the membrane." ...

The nicotinic acetylcholine (ACh) receptor, a ligand-gated ion channel. The receptor molecule is depicted as embedded in a rectangular piece of plasma membrane, with extracellular fluid above and cytoplasm below. Composed of five subunits (two , one B, one 7, and one 5), the receptor opens a central transmembrane ion channel when ACh binds to sites on the extracellular domain of its a subunits. 

With the larger Ms(calix) crown (3.127),65 two dynamic processes are observed. The intermolecular association/disassociation equilibrium in which the complex equilibrates with the uncomplexed ligand and free metal cation is slow on the NMR time scale. The complex also exhibits a faster intramolecular vibration of the metal cation from one binding site to another (Scheme 3.26). Compound 3.127 is also interesting because the mechanism of this fast, intramolecular cation shuttling process may have important implications on the analogous movement of metal cations through transmembrane ion channels (Section 2.2). 

From your answers to question 3.6 or otherwise, suggest artificial systems that mimic (a) some of the properties of the natural ionophores and (b) features of transmembrane ion channels. 

Fig. 5.11 An acid sensitive transmembrane ion channel-forming protein [28]...

Primary sequences of proteins known, or likely, to incorporate membrane-spanning regions are a useful place to start when investigating the structural aspects of transmembrane ion channels. Once a sequence has been identified it is possible to generate a secondary structure by matching regions of the protein with known... 

A more systematic approach has been taken by the Fyles group. In an effort to understand the important structure-activity relationships underpinning simple ion transport, alkyl chains of variable lengths, polyethers and amino acids have been linked by esters to produce an extensive library, examples of which are to be seen in Fig. 5.17 [60], The transport rates and selectivities of these compounds gave valuable information on the essential and desirable characteristics of these, the simplest, transmembrane ion channels. 

Iqbal KSJ et al (2007) Artificial transmembrane ion channels from commercial surfactants. Chem Commun 3951-3953... 

Kobuke Y, Nagatani T (2001) Transmembrane ion channels constructed of cholic acid derivatives. J Org Chem 66 5094-5101... 

Ghadiri, M. R., Granja, J. R., and Buehler, L. K. (1994). Artificial transmembrane ion channels from self-assembling peptide nanotubes. Nature 369, 301-304. 

The glutamic acid residue renders this compound soluble in alkaline media stacking to form nanotubes occurs after acidification (Scheme 1). The more hydrophobic side chains in cyclo[-(Trp-D-Leu)3-Gln-D-Leu-] even enabled the construction of a transmembrane ion channel with a proton transport activity similar to that of gramicidin A or amphotericine B 6]. Measurements of singlechannel conductivity showed fast transport of sodium and potassium ions the channels pore diameter of 7.5 A led to weak potassium selec-tiv-ity [7]. 

The conformations considered above have referred to polypeptide chains all of whose residues are achiral, such as (Gly) or (Aib) , or have the same chirality, L or n, throughout. There is an important class of polypeptides, of which the transmembrane ion-channel gramicidin A (GA) is an example, in which the chirality of adjacent residues alternates along the chain. Although a-helix structures are possible (Hesselink and Scheraga, 1972), l,d sequences favor new kinds of conformations. The normal-mode analyses of these structures (Naik and Krimm, 1986a) permit a detailed characterization of their vibrational spectra. 

Recently it has been shown that single-walled carbon nanotubes and fullerenes are capable of blocking cellular transmembrane ion channels [9]. Given global interest in the potential toxicity of nanomaterials, including C6o, the macrocyclic... 

The acetylcholine receptor is also a transmembrane ion channel, and it is composed of four different subunits (671. Chimeric mRNA from recombinant clones of different species has been expressed in Xenopus oocytes. This is the target of nicotine, a classical agonist for discriminating among receptor subtypes. This receptor has not been evaluated as a resistance mechanism, although it is involved in the process of poisoning by many insecticides. 

Polytheonamide B (47), the largest nonribosomal peptide of marine origin isolated from T. swinhoei, showed the potent cytotoxicity by forming transmembrane ion channels. ... 

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