EFFECTS ON PERMEABILITY AND ACTIVE TRANSPORT 171 



zymes by iodoacetate at 1.5 mM and a pH of 4.5 observed by Aldous (1952) 

 may be explained by a nonspecific acid effect, especially since some of these 

 enzymes are not readily inhibited by iodoacetate. 



EFFECTS ON PERMEABILITY AND ACTIVE TRANSPORT 



Cellular function usually depends in one way or another on the transport 

 of substances into or out of the cell, and excitable tissues apparently have 

 specialized systems for membrane transport. It will therefore be necessary 

 to discuss the inhibition of these general processes before taking up indi- 

 vidual cellular activities. Inasmuch as membrane transport inhibition was 

 treated very cursorily in Volume I (page 439), the opportunity will now 

 be taken to discuss some general aspects of this problem, especially as it 

 relates to the effects of SH reagents and other irreversible or slowly irre- 

 versible inhibitors. 



Mechanisms of Inhibition of Transport and Accumulation 



The transport of a substance through the plasma membrane or across a 

 layer of cells may be passive (simple diffusion), facilitated (diffusion of a 

 complex with a carrier), or active (requiring energy from metabolism). In 

 all cases the inhibitor can produce its effect by acting either on the meta- 

 bolic systems involved in supplying energy for transport or the mainten- 

 ance of the membrane, or on the membrane or the transport system direct- 

 ly. For example, the permeability to a substance can be altered by an attack 

 on the membrane and its structure, or secondarily by disturbing metabolism. 

 Some inhibitors, such as cyanide or fluoroacetate, undoubtedly act mainly 

 by the latter mechanism, whereas SH reagents are much more apt to act 

 also on the membrane, since the membrane proteins contain SH groups 

 probably important in maintaining the integrity of the membrane. Active 

 transport systems may for convenience be considered as consisting of two 

 parts: the exergonic reactions providing the required energy (usually oxida- 

 tions coupled with ATP generation) and the endergonic reactions by which 

 the substance is transported and the energy utilized (the functional trans- 

 port system itself). Inhibitors are often used to detect active transport 

 and are assumed to reduce the supply of energy, but many inhibitors can 

 also affect the transport system directly, i.e., either the exergonic or ender- 

 gonic phase may be depressed. Inhibitors reducing ATP generation (e.g. 

 2,4-dinitrophenol) can be thought of as exerting a rather nonspecific effect 

 with respect to transport, since any cell function requiring energy will be 

 depressed eventually, whereas inhibition of the endergonic system may be 

 more selective, blocking transport and leaving other cell functions intact 

 (except as they may be secondarily modified), or even blocking one trans- 



