Calcium messenger system mechanism

The cellular mechanism of lead nephrotoxicity appears to be due to an alteration of calcium homeostasis. Lead (Pb ) competes with calcium (Ca " ") for transport, binding to calmodulin and at other cell calcium regulatory sites. Lead can accumulate in mitochondria using the calcium transporter and disrupt respiration. Interactions of lead with calmodulin can result in a disruption of the calcium messenger system to adversely affect normal cell function. The nuclear inclusion bodies may also alter the cellular function of DNA, although this interaction has not been fully elucidated. 

There are numerous second messenger systems such as those utilizing cyclic AMP and cyclic GMP, calcium and calmodulin, phosphoinosiddes, and diacylglerol with accompanying modulatory mechanisms. Each receptor is coupled to these in a variety of ways in different cell types. Therefore, it can be seen that it is impractical to attempt to quantitatively define each stimulus-response mechanism for each receptor system. Fortunately, this is not an... 

The mechanism of action for aluminum toxicity is not known, but the element is known to compete in biological systems with cations, especially magnesium (MacDonald and Martin 1988) despite an oxidation state difference, and to bind to transferrin and citrate in the blood stream (Gannot 1986). It may also affect second messenger systems and calcium availability (Birchall and Chappell 1988), and irreversibly bind to cell nucleus components (Crapper-McLachlan 1989 Dryssen et al. 1987). Aluminum has also been shown to inhibit neuronal microtubule formation. However, much more work is needed before a mechanism can be proposed. 

Disruption of Ca Homeostasis and Neurological Effects. Neurological and/or neurodevelopmental effects from exposure to PCBs also have been hypothesized to involve interference with calcium homeostatic mechanisms and intracellular second messenger systems by PCB congeners that are not effective Ah receptor agonists (see reviews by Kodavanti and Tilson 1997 Tilson and Kodavanti 1998 Tilson et al. 1998). In agreement with structure-activity relationships observed for PCB effects on dopamine levels in pheochromocytoma cells (Shain et al. 1991), 2,2 -diCB altered intracellular calcium homeostasis in cultured rat cerebellar granule cells (increased free calcium levels and inhibited calcium... 

The activation of the calcium second messenger system by hormones, neurotransmitters, iocal mediators, and sensory stimuii is very important in reguiating VSM contraction. Severai signai transduction mechanisms modulate intracellular calcium concentration and, therefore, the state of vascular tone. These calcium second messenger systems are the phosphatidyiinositol (PIP2)/Gq protein-coupled pathway, the cyclic adenosine monophosphate (cAMP)/Gs protein-coupied pathway, and the NO/cyclic guanosine monophosphate (cGMP) pathway. 

Whereas Hi receptors are involved with positive effects, H2 receptors appear to mainly mediate suppressive activities of histamine including gastric acid secretion, heart contraction, cell proliferation, differentiation, and some effects on the immune response. H2 receptors are coupled to the adenylate cyclase as well as the phosphoinositide second messenger systems via separate GTP-dependent mechanisms, but H2-dependent effects, particularly those of the central nervous system, are predominantly mediated through cAMP. It has been shown that receptor binding stimulates activation of c-Fos, c-Jun, PKC, and P70S6 kinase. Alternative signaling pathways have been reported (Fig. 3.7). These include a receptor-mediated increase in intracellular Ca and/or IP3 levels in HL-60 human promyelocytic leukemia cells and an increase in cAMP and inhibition of release of arachidonic acid in Chinese hamster ovary (CHO) cells transfected with rat cDNA and induced by calcium ionophore. 

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