Respiratory coupling sites

Finally, the intermediate P-to-O ratio obtained with succinate indicates that a coupling site occurs in complex III, but probably not in complex II. Thus, the respiratory chain appears to have three distinct coupling sites for ATP synthesis. 

In a study pubUshed in 1964, Rossi and Lehninger [20] extended the observations made by Chance in 1956 on the stimulation of oxygen consumption by mitochondria, and established that approximately 2Ca were transported into mitochondria as a couple of electrons traversed each one of the respiratory chain segments which were called, in the terminology of the 1960 s, coupling sites . They thus concluded that the Ca /oxygen ratio for the full respiratory chain span was 6. In other words, mitochondria use the same amount of respiratory energy to phosphorylate one ADP molecule or to transport across the membrane 2Ca ". ... 

A slowly progressive congenital neuromuscular disorder was reported in which the respiratory chain-linked energy transfer at a level common to all three energy coupling sites of respiratory chain was defective.52 Uncouplers of mitochondrial oxidative phosphorylation (2,4-dinitrophenol and carbonylcyanide-m-chlorophenylhydrazone) (5) produced mitochondrial myopathy in rats.53... 

Whereas these studies primarily emphasize the role of energy-linked transhydrogenase in the supply of reducing equivalents at the expense of energy, other authors 146, 155) regard the enzyme as a component of a fourth coupling site of the respiratory chain, which, when catalyzing the reduction of NAD+ by NADPH, may drive ion translocations 147, 157) and ATP synthesis 119),... 

When mitochondria from bovine heart were solubilized by treatment with mild detergents it was possible to separate and purify the sections of the respiratory chain referred to earlier as coupling sites 1, 2 and 3. These were named Complex I (NADH-ubiquinone oxidoreductase), Complex III (ubiquinol-cytochrome c ox-idoreductase, cytochrome bci complex) and Complex IV (cytochrome c oxidase) [17], and have since been characterized as independent entities, although it is now recognized that these three complexes co-assemble with specific stoichiometry to form respiratory chain supercomplexes or respirasomes in fungal, plant and mammalian mitochondria [18-20]. There is also evidence that succinate-ubiquinone oxidoreductase (which was purified alongside the other complexes and named Complex II [21]) forms a tight association with Complex III in yeast mitochondria [22]. 

The number of molecules of phosphate esterified (or ATP molecules synthesized from ADP and Pi) per atom of oxygen consumed is called the P 0 ratio. The P/O ratio for NADH oxidation is therefore 3. However for the oxidation of succinate via succinate dehydrogenase, since the part of the respiratory chain between NADH and ubiquinone is by-passed (page 217) only two coupling sites are traversed and the P/O ratio for succinate is 2. Similarly, if isolated mitochondria are presented with ascorbic acid which reacts directly with cytochrome c, the first two coupling sites are by-passed and the P/O ratio for the oxidation of ascorbic acid is 1. These considerations will be applied later to calculate the number of ATP molecules that can be synthesized during the oxidation of a molecule of glucose or of fatty acids. 

A second group of widely used inhibitors is represented by (a) the barbiturate am)rtal and the fish poison rotenone, which inhibit at the level of the first coupling site, (b) the antibiotic antimycin A. which blocks the respiratory chain in the region of c)Ttochrome b, and (c) cyanide, which interacts with cytochrome oxidase and blocks the chain at its end. 

There are various opioid receptors the three major classes of opioid receptors are mu (p), delta (5) and kappa (k) receptors. The p, receptor is the principal pain-modulating site in the CNS, mediating the action of morphine. There is considerable interest in the K receptor, which mediates a sedating analgesia with decreased addiction liability and respiratory depression and which allows for some structural flexibility. Unfortunately, the K receptor seems to be coupled to the sigma (a) receptor, which is implicated in psychotomimetic and dysphoric side effects. 

---