ATPases stimulation

Niclosamide is a salicylamide derivative. Its mechanism of action could be based on inhibition of oxidative phosphorylation or on its ATPase stimulating action. The scolices and segments, but not segments of the ova, are rapidly killed. Niclosamide is minimally absorbed from the gastrointestinal tract and excreted, mostly unchanged, in the faeces. It is generally well tolerated with occasional gastrointestinal disturbances. Skin eruptions have been reported. 

For many years, niclosamide (Niclocide) was widely used to treat infestations of cestodes. Niclosamide is a chlorinated salicylamide that inhibits the production of energy derived from anaerobic metabolism. It may also have adenosine triphosphatase (ATPase) stimulating properties. Inhibition of anaerobic incorporation of inorganic phosphate into ATP is detrimental to the parasite. Niclosamide can uncouple oxidative phosphorylation in mammalian mitochondria, but this action requires dosages that are higher than those commonly used in treating worm infections. 

As seen in Figure 18.6, the maximal extent of P-gp ATPase stimulation, which correlates with the rate of intrinsic transport, ln, decreases as the affinity of drugs to the transporter increases or as the free energy of binding, AG, decreases. Molecules with low affinity are thus transported more rapidly and tend to be smaller (Figure 18.7). 

Norepinephrine also increases the permeability of BAT and skeletal mnscle to sodinm. Becanse an increase of intracellnlar Na is potentially toxic to cells, Na, K -ATPase is stimnlated to transport Na+ ont of the cell in exchange for K. The increased hydrolysis of ATP by Na, K -ATPase stimulates the oxidation of fnels and the regeneration of more ATP and heat from oxidative phosphorylation. Over a longer time conrse, thyroid hormone also increases the level of Na, K -ATPase and many of the enzymes of fuel oxidation. Because even at normal room temperatnre ATP ntihzation by Na, K -ATPase acconnts for 20% or more of our basal metabohc rate (BMR), changes in its activity can cause relatively large increases in heat prodnction. 

Studies with ATPase inhibitors also suggest that different proteins might be involved in catalyzing the breakdown of ATP. Oligomycin, chlorpromazine, and azide inhibit the ATPase activity elicited by both magnesium and NAD. In contrast, amytal interferes only with the ATPase activity revealed by NAD. These observations have been interpreted to suggest that the ATPase stimulated by NAD is different from that stimulated by magnesium. 

Contraction of muscle follows an increase of Ca " in the muscle cell as a result of nerve stimulation. This initiates processes which cause the proteins myosin and actin to be drawn together making the cell shorter and thicker. The return of the Ca " to its storage site, the sarcoplasmic reticulum, by an active pump mechanism allows the contracted muscle to relax (27). Calcium ion, also a factor in the release of acetylcholine on stimulation of nerve cells, influences the permeabiUty of cell membranes activates enzymes, such as adenosine triphosphatase (ATPase), Hpase, and some proteolytic enzymes and facihtates intestinal absorption of vitamin B 2 [68-19-9] (28). 

However, release of ADP and P from myosin is much slower. Actin activates myosin ATPase activity by stimulating the release of P and then ADP. Product release is followed by the binding of a new ATP to the actomyosin complex, which causes actomyosin to dissociate into free actin and myosin. The cycle of ATP hydrolysis then repeats, as shown in Figure 17.23a. The crucial point of this model is that ATP hydrolysis and the association and dissociation of actin and myosin are coupled. It is this coupling that enables ATP hydrolysis to power muscle contraction. 

In resting muscle the high concentration of ADP does not decrease the proton gradient effectively and the high membrane potential slows electron transport. ADP, formed when ATP is hydrolyzed by myosin ATPase during contraction, may stimulate electron transport. However, the concentration of ATP (largely as its Mg salt) is buffered by its readily reversible formation from creatine phosphate catalyzed in the intermembrane space, and in other cell compartments, by the various isoenzymes of creatine kinase (reviewed by Walliman et al., 1992). 

The thyroid is able to concentrate T against a strong electrochemical gradient. This is an energy-dependent process and is linked to the Na -K ATPase-dependent thyroidal T transporter. The ratio of iodide in thyroid to iodide in serum (T S ratio) is a reflection of the activity of this transporter. This activity is primarily controlled by TSH and ranges from 500 1 in animals chronically stimulated with TSH to 5 1 or less in hy-pophysectomized animals (no TSH). The T S ratio in humans on a normal iodine diet is about 25 1. 

The Ca transport and Ca -stimulated ATPase activity of sarcoplasmic reticulum is inhibited by 10-30nmol dicyclohexylcarbodiimide per mg protein in a Ca free medium [372]. A23187 enhanced the sensitivity of the enzyme to DCCD, while Ca or Sr at micromolar concentrations prevented the inhibition. Since Ca -loaded vesicles retained their sensitivity to DCCD in a Ca -free medium, the reactivity of the enzyme with DCCD is controlled by the occupancy of the high-affinity Ca sites on the cytoplasmic surface of the membrane. 

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