Calcium-binding sites correlations

However, there have been some contradictory results. It has been reported that some modifiers do not compete with the cytotoxic agent for binding to P-gp even though they act as substrates for it [77]. In some resistant cell tines there was no correlation between an increase in MDR and the P-gp levels [79-81], The calcium channel blocker SR3357 (2) - which is 4—5 times more potent than verapamil - was shown not to compete for the binding site of the labeled [3H]-azidopine on P-gp whereas verapamil did. SR3357 did not bind to P-gp, but to a 65-kDa protein. Inter-... 

Since P-endorphin is located within the hypothalamus and the pituitary, and has a relatively longer duration of action, it tends to be viewed as a neurohormone. Enkephalins, on the other hand, are more extensively distributed, are very rapidly degraded, and are primarily located in synaptosomal areas. The additional observation that enkephalin release following depolarization of brain (and intestinal) tissues is calcium dependent makes it more realistic to categorize them as neurotransmitters or modulators of synaptic function. Binding sites (receptors) for opioids are found, particularly in synaptosomal brain fractions. The enkephalins are located in neurons whose distribution correlates well with that of the receptors. In fact, regional distribution of peptides and their receptors are closely parallel, as would be predicted for a neurotransmitter system. 

The next stage involves the synthesis of specific calcium-binding proteins, typified by the intestinal CaBP discussed in Section 62.1.3.4.5, which probably stimulates the transport of calcium. The role of the protein in vitamin D-dependent absorption of calcium is supported by the good correlation between the concentration of CaBP and the rate of calcium absorption. Under conditions of low calcium or phosphorus diets, chicks and other animals produce more intestinal CaBP to increase the efficiency of uptake of calcium. In general, adaptation to a low calcium diet involves increased synthesis of l,25-(OH)2D3 and the intestinal CaBP. Lowered requirements for calcium in old age are manifested by lower levels of both factors. Advances have been made in the localization of the cellular sites of l,25-(OH)2D3 in target tissue. Receptor proteins have been extracted, and, in the case of the chick intestinal receptor, purified to homogeneity." The ability of l,25-(OH)2D3 to stimulate absorption of calcium is blocked reversibly by inhibitors of RNA and protein synthesis. This suggests that l,25-(OH)2D3 functions by a nuclear mechanism. 

Some members of calcium channel blockers, such as nicardipine (40) and ni-modipine (41), were identified as potent MDR antagonists. This early work stressed the lack of correlation between the calcium channel blocking and anti-MDR potencies [75]. It has been reported that DHPs bind to a site that is allosterically coupled to the receptor site which binds anticancer agents and other MDR reversal agents [76,77]. DHPs are well recognized as privileged structure for their multi-receptor affinity [78,79]. 

Calcium channel blockers bind specifically to receptor sites associated with the voltage-dependent calcium channels [31,32]. These blockers inhibit calcium uptake [33,34] and block smooth muscle contraction [35,36]. All these three activities of calcium channel blockers have been found to be mutually correlated. For ten known calciiun channel blockers (Table 4), Papaionnou et al. [37] derived the correlations ... 

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