Calmodulin, calcium-cadmium

Osteomalacia and osteoporosis are reported primarily in patients (95% females) with itai-itai disease, and osteomalacia has been observed in cadmium industry workers, the majority of whom are male (Goyer 1991). While the mechanisms for these effects are not well known, cadmium disruption of calcium metabolism may be important. One of the manifestations of renal injury in cadmium-exposed populations is calcuria and negative calcium balance. It is not clear whether these effects on calcium metabolism occur secondary to renal injury, or whether there is a direct effect on calcium pathways (see discussion of calmodulin-calcium-cadmium interactions in Sect. B.I). 

Metals with a similar ionic radius to calcium ( 1 0.2 A, e.g. cadmium, lead, mercury), are able to substitute for calcium in calmodulin343643. One main consequence of this substitution is that the metal-binding sites of calmodulin become filled with metals other than calcium and thus less calcium is required to activate... 

The toxic effects of cadmium (Cd) are due to the inactivation of enzymes containing sulfhydryl groups and the uncoupling of oxidative phosphorylation in mitochondria (Teissedre et al. 1994). Cadmium may also compete with other metals such as zinc and selenium for inclusion into metal-loenzymes, and it may compete with calcium for binding sites on regulatory proteins such as calmodulin (Hu 1998). The OIV established the maximum level of cadmium in wine at 10 pg/L. 

Calmodulin is a major intracellular calcium-binding protein which regulates a wide variety of calcium-dependent processes (Cheung 1982). The binding of calcium to calmodulin induces a conformational change in the protein to an active form. The calcium-calmodulin complex is then capable of regulating a host of other molecules such as phosphodiesterase, adenylate kinase, protein kinases, and Ca-ATPase. Cadmium has been shown to... 

Chen Y-C, Smith JB (1992) A putative lectin-binding receptor mediates cadmium-evoked calcium release. Toxicol Appl Pharmacol 117 249-256 Cherian MG, Goyer RA, Delaquerriere-Richardson L (1976) Cadmium-metal-lothionein-induced nephrotoxicity. Toxicol Appl Pharmacol 38 399-408 Cheung WY (1982) Calmodulin. Sci Am 246 62-70... 

Because of our interest in utilizing Cd NMR spectroscopy as a probe for calcium sites in biological systems (42,43,49,51), we have been interested in the isotropic Cd chemical shifts in these compounds. In the systems studied (Concanavalin A (42), Parvalbumin (43), Troponin C (50),. Calmodulin (49), and Insulin (51)), replacing calcium with cadmium places cadmium in an environment in which all of the atoms in the first coordination sphere are oxygens. The cadmium is assumed to be six coordinate. The isotropic chemical shifts for these compounds (82) fall into a characteristic range of chemical shifts from -85 to -130 ppm with respect to 0.1 M Cd(C104)2 To date, there are no model compounds that can be studied in aqueous solutions which have isotropic shifts within this range. 

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