Channels, and Carriers

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. 

With the adequacy of lipid bilayer membranes as models for the basic structural motif and hence for the ion transport barrier of biological membranes, studies of channel and carrier ion transport mechanisms across such membranes become of central relevance to transport across cell membranes. The fundamental principles derived from these studies, however, have generality beyond the specific model systems. As noted above and as will be treated below, it is found that selective transport... 

Clear understanding of the differences between channels and carriers only came two decades later with the realization that the turnover number, the rate of maximal ion permeation, for the fastest carrier was at least two orders of magnitude lower that of a typical channel (see Hille, 1984, and below). In retrospect, it is odd to find that the experiments underpinning the two conceptual pillars (channels and carriers) which nurtured membrane transport biology through the second half of the 20th... 

PUMPS, CHANNELS, AND CARRIERS FROM "ACTIVE PATCHES" TO MEMBRANE... 

The distinction between facilitated diffusion through channels and carrier-mediated transport is somewhat artificial/ but may be justified on the basis of specificity. For example/ 3-lactams in general can pass through nonselective bacterial outer membrane porin (e.g./ OmpF) channels via passive diffusion/ whereas imipenem (and related zwitterionic carbapenems) can also utilize OprD channels/ which preferentially recognize basic amino acids and dipeptides. The identification of mutants that selectively confer imipenem resistance suggests that more intimate protein-drug associations are involved in carrier-mediated transport than in facilitated diffusion/ which may be limited only by pore diameter. 

Targets for drag action are the sites where a drug interacts with part of a body cell or other body component. These include receptors in cell membranes or within the cell itself, ion channels and carrier proteins in cell membranes and enzymes in body fluids. 

A limited improvement in this context may be possible by the use of more stable proteins, e.g. from thermophilic bacteria. However, many principles demonstrated by nature could be transposed to sensor development. For example, biomimetic channel and carrier molecules could be used in conjunction with stabilized lipid membranes to prepare sensitive and selective electrochemical transducers which embodied the principle of intrinsic amplification by depolarization. The use of artificial receptor sites would probably result in a substantial reduction of the desired selectivity coefficients, but this could easily be compensated by the application of array processing for background correction. 

The cell controls the expression and activity of membrane proteins that increase the movement of specific molecules across the membrane. These proteins can be classified broadly according to the energy consumed as those governing facilitated diffusion or active transport. They may also be categorized as channels that form an aqueous pore in the membrane through which solutes can pass or carriers that selectively bind a molecule to effect its translocation. The term transporter is currently used to refer to both channels and carriers, although some authors use it synonymously with carrier. 

In addition to passive diffusion, channels, and carrier proteins, a fourth mechanism of breaching biological membranes is provided by vesicle-mediated transport, which can also be used for drug delivery. Endocytosis refers to the uptake of cell surface constituents by the formation of vesicles from the plasma membrane. This process can be subclassified into phagocytosis, the engulfment of particles, and pinocytosis, the engulfment of fluid. 

In contrast to the channel and carrier proteins described earlier, some carrier or transporter proteins utilize energy, in the form of ATP, either directly or indirectly to move substrates against their concentration gradient. In the case of carriers that use energy indirectly, also known as secondary active transporters,... 

Interestingly, the voltage-gated CLC has classic channel characteristics, whereas CFTR has characteristics of an ion channel and a carrier. Apparently, in the case of CLC, the classical definition for channels and carriers is mixed, suggesting that the two types of ion transport mechanisms share common features. 

We can expect to gain greater understanding of the role of lipid in altering conductances by using channels and carriers as probes of membrane structure. This effort is actually well under way at present. The interested reader is referred to Benz et al. [36] for an introduction to this problem of using carriers as probes. 

Chapter 4. Channels and carriers in lipid bilayers, by J.E. Hall... 

Probes for the Na" channel and the Na /H antiporter amiloride analogs Na /K -ATPase ouabain probes Probes for channels and carriers glibenclamide conjugates for the ATP-dependent channel, apamin probes for small-conductance Ga -activated channels. 

Probes for GI channels and carriers Ivermectin probes for glutamate-gated GI channels, stilbene disulfonates (anion-transport Inhibitors),... 

---