Transmembrane channel

Channels Transmembrane pores selectivity for solutes depends on biophysical properties that are actively regulated... 

Voltage-gated ion channels Transmembrane ion channels regulated by changes in membrane potential... 

Fig. 3. (a) Chemical stmcture of a synthetic cycHc peptide composed of an alternating sequence of D- and L-amino acids. The side chains of the amino acids have been chosen such that the peripheral functional groups of the dat rings are hydrophobic and allow insertion into Hpid bilayers, (b) Proposed stmcture of a self-assembled transmembrane pore comprised of hydrogen bonded cycHc peptides. The channel is stabilized by hydrogen bonds between the peptide backbones of the individual molecules. These synthetic pores have been demonstrated to form ion channels in Hpid bilayers (71). 

Verapamil. Verapamil hydrochloride (see Table 1) is a synthetic papaverine [58-74-2] C2qH2 N04, derivative that was originally studied as a smooth muscle relaxant. It was later found to have properties of a new class of dmgs that inhibited transmembrane calcium movements. It is a (+),(—) racemic mixture. The (+)-isomer has local anesthetic properties and may exert effects on the fast sodium channel and slow phase 0 depolarization of the action potential. The (—)-isomer affects the slow calcium channel. Verapamil is an effective antiarrhythmic agent for supraventricular AV nodal reentrant arrhythmias (V1-2) and for controlling the ventricular response to atrial fibrillation (1,2,71—73). 

Calcium channel blockers reduce arterial blood pressure by decreasing calcium influx, resulting in a decrease in intracellular calcium (236,237). The arterial smooth muscle tone decreases, thereby decreasing total peripheral resistance. The increase in vascular resistance in hypertension is found to depend much on calcium influx. Calcium channel blockers reduce blood pressure at rest and during exercise. They decrease the transmembranous calcium influx or entry that lead to a net decrease of intracellular calcium and therefore the vascular tone falls, as does blood pressure. 

Verapamil (Table 1), the first slow channel calcium blocker synthesized to selectively inhibit the transmembrane influx of calcium ions into cells, lowers blood pressure in hypertensive patients having good organ perfusion particularly with increased renal blood flow. Sustained-release verapamil for once a day dosing is available for the treatment of hypertension. Constipation is a prominent side effect. Headache, dizziness, and edema are frequent and verapamil can sometimes cause AV conduction disturbances and AV block. Verapamil should not be used in combination with -adrenoceptor blockers because of the synergistic negative effects on heart rate and contractile force. 

Figure 12.S Schematic diagram of the bacteriorhodopsin molecule illustrating the relation between the proton channel and bound retinal in its tram form. A to E are the seven transmembrane helices. Retinal is covalently bound to a lysine residue. The relative positions of two Asp residues, which are important for proton transfer, are also shown. (Adapted from R. Henderson et al.,...

Since the outside of the barrel faces hydrophobic lipids of the membrane and the inside forms the solvent-exposed channel, one would expect the P strands to contain alternating hydrophobic and hydrophilic side chains. This requirement is not strict, however, because internal residues can be hydrophobic if they are in contact with hydrophobic residues from loop regions. The prediction of transmembrane p strands from amino acid sequences is therefore more difficult and less reliable than the prediction of transmembrane a helices. 

The polypeptide chain of the bacterial channel comprises 158 residues folded into two transmembrane helices, a pore helix and a cytoplasmic tail of 33 residues that was removed before crystallization. Four subunits... 

Figure 12.9 Schematic diagram of the stmc-ture of a potassium channel viewed perpendicular to the plane of the membrane. The molecule is tetrameric with a hole in the middle that forms the ion pore (purple). Each subunit forms two transmembrane helices, the inner and the outer helix. The pore heJix and loop regions build up the ion pore in combination with the inner helix. (Adapted from S.A. Doyle et al., Science 280 69-77, 1998.)...

The C-terminal transmembrane helix, the inner helix, faces the central pore while the N-terminal helix, the outer helix, faces the lipid membrane. The four inner helices of the molecule are tilted and kinked so that the subunits open like petals of a flower towards the outside of the cell (Figure 12.10). The open petals house the region of the polypeptide chain between the two transmembrane helices. This segment of about 30 residues contains an additional helix, the pore helix, and loop regions which form the outer part of the ion channel. One of these loop regions with its counterparts from the three other subunits forms the narrow selectivity filter that is responsible for ion selectivity. The central and inner parts of the ion channel are lined by residues from the four inner helices. 

Like the photosynthetic reaction center and bacteriorhodopsin, the bacterial ion channel also has tilted transmembrane helices, two in each of the subunits of the homotetrameric molecule that has fourfold symmetry. These transmembrane helices line the central and inner parts of the channel but do not contribute to the remarkable 10,000-fold selectivity for K+ ions over Na+ ions. This crucial property of the channel is achieved through the narrow selectivity filter that is formed by loop regions from thefour subunits and lined by main-chain carbonyl oxygen atoms, to which dehydrated K ions bind. 

FIGURE 10.32 The structures of (a) S-eudotoxiu (two views) from Bacillus thuringiensis and (b) diphtheria toxin from Cmynehacterium diphtheriae. Each of these toxins possesses a bundle of a-hehces which is presumed to form the trausmembraue channel when the toxin Is Inserted across the host membrane. In S-endotoxln, helix 5 (white) Is surrounded by 6 helices (red) In a 7-hellx bundle. In diphtheria toxin, three hydrophobic helices (white) lie at the center of the transmembrane domain (red). 

FIGURE 10.33 The structure of the heptameric channel formed by o -hemolysin. Each of the seven subunits contributes a /3-sheet hairpin to the transmembrane channel. 

Recently, a variety of natural peptides that form transmembrane channels have been identified and characterized. Melittin (Figure 10.35) is a bee venom toxin peptide of 26 residues. The cecropins are peptides induced in Hyalophora cecropia (Figure 10.36) and other related silkworms when challenged by bacterial infections. These peptides are thought to form m-helical aggregates in mem-... 

All of the transport systems examined thus far are relatively large proteins. Several small molecule toxins produced by microorganisms facilitate ion transport across membranes. Due to their relative simplicity, these molecules, the lonophore antibiotics, represent paradigms of the mobile carrier and pore or charmel models for membrane transport. Mobile carriers are molecules that form complexes with particular ions and diffuse freely across a lipid membrane (Figure 10.38). Pores or channels, on the other hand, adopt a fixed orientation in a membrane, creating a hole that permits the transmembrane movement of ions. These pores or channels may be formed from monomeric or (more often) multimeric structures in the membrane. 

Mitochondria are surrounded by a simple outer membrane and a more complex inner membrane (Figure 21.1). The space between the inner and outer membranes is referred to as the intermembrane space. Several enzymes that utilize ATP (such as creatine kinase and adenylate kinase) are found in the intermembrane space. The smooth outer membrane is about 30 to 40% lipid and 60 to 70% protein, and has a relatively high concentration of phos-phatidylinositol. The outer membrane contains significant amounts of porin —a transmembrane protein, rich in /3-sheets, that forms large channels across the membrane, permitting free diffusion of molecules with molecular weights of about 10,000 or less. Apparently, the outer membrane functions mainly to... 

---