Increased Cellular Calcium Influx

Another common cellular target of palytoxin and TPA is the EGF receptor. It has been described that palytoxin inhibited the binding of EGF to low- and high-affinity receptors in a manner independent of protein kinase C. Moreover, picomolar concentrations of palytoxin inhibited EGF binding in the absence of cytosolic calcium increase. Further studies indicated that the palytoxin effects on EGF receptor were not due to common secondary effects of sodium influx, including membrane depolarization, changes in intracellular pH, or inhibition of protein synthesis. ... 

Coetzee and Opie (1988, 1992) have suggested that the cellular calcium overload induced by oxidant stress is mediated by an increase in calcium influx through the L-type calcium channel. However, a number of other studies, using different radical-generating systems, experimental conditions and species, have described no significant effects on the calcium channel over the period of exposure necessary to induce cellular calcium overload (Bhatnagar etal., 1990 Shattock etal., 1990 Beresewicz... 

Mechanism of Action. These drugs are known to increase the seizure threshold and limit the spread of electrical activity in the brain, but their exact cellular mechanism is unknown. They may exert their beneficial effects by decreasing calcium influx in certain thalamic neurons. The spontaneous, rhythmic entry of calcium into thalamic neurons may be responsible for initiating partial seizures, and the succinimides prevent their onset by blunting calcium influx. Additional research is needed to elaborate on this theory. 

The addition of All to the target tissues under discussion leads to three changes in cellular calcium metabolism (1) a transient increase in cytosolic calcium (2) a reduction in total cell calcium and (3) a sustained increase in the rate of calcium influx across the plasma membrane. Each of these changes in cellular calcium metabolism is discussed below. 

Fig. 1. All-induced alterations in cellular calcium metabolism. Indicated are the increase in cytosolic calcium (upper left panel) enhanced calcium influx (upper right panel) the loss of total cell calcium (lower right panel) and the calculated compensatory increase in calcium efflux as a function of time after All addition (at arrow).

This obvious dependence on extracellular calcium is somewhat unexpected because (1) the sustained enhancement of calcium influx rate is adequately balanced by an increase in calcium efflux rate so that (2) the calcium concentration in the bulk cytosol is maintained near the basal value. This apparent paradox may be resolved by a model [54] which postulates that during the sustained phase of cellular response the high rate of calcium cycling across the plasma membrane raises the calcium concentration in a region just below the plasma membrane, often called the submembrane domain (see Rasmussen and Barrett, Chapter 4). Because the elevated calcium level in this domain is not conducted into the bulk cytosol, it cannot activate calcium-dependent response elements in the cytosol. Rather it regulates the activity of calcium-sensitive, plasma membrane-associated enzymes such as the calcium pump and PKC, the previously described phospholipid-dependent, calcium-activated protein kinase. 

The physiological role of PHB/polyP complexes has not been established, but bacterial cells like eukaryotic cells maintain low internal Ca2+,101-103,112 and there is increasing evidence pointing to calcium involvement in a number of important cellular functions, such as chemotaxis, cell division, heat shock, pathogenicity, and differentiation.104-107 Systems for calcium export have been identified.108-109 Mechanisms for calcium entry are less well known. An L-type channel was reported in Bacillus subtilis,n0 lu and Jones et al. and Holland et al.103,112 recently demonstrated the presence of a putative Ca2+ influx channel in stationary phase E. coli,... 

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