Cytosolic Ca"+ concentration

Figure 1. Simplified schematic of receptor-mediated signal transduction in neutrophils. Binding of ligand to the receptor activates a guanine-nucleotide-binding protein (G protein), which then stimulates phospholipase C. Phosphatidylinositol 4,5-bis-phosphate is cleaved to produce diacylglycerol (DAG) and inositol 1,4,5-trisphosphate (IP3). DAG stimulates protein kinase C. IP3 causes the release of Ca from intracellular stores, which results in an increase in the cytosolic Ca concentration. This increase in Ca may stimulate protein kinase C, calmodulin-dependent protein kinases, and phospholipase A2. Protein phosphorylation events are thought to be important in stimulating degranulation and oxidant production. In addition, ionic fluxes occur across the plasma membrane. It is possible that phospholipase A2 and ionic channels may be governed by G protein interactions. ...

In the extracellular region, the concentration is over lO M, which is very high in comparison to the free cytosolic Ca concentration. The cell membrane contains various channels that enable Ca influx from the extracellular region into the cytosol. One of the primary functions of Ca entry is to charge up the internal stores, which can then release an internal Ca signal. 

Opening of leads to a local increase in the cytosolic Ca concentration from 10 M to 10 M. In this concentration region, the Ca transport systems mentioned above work very efficiently. However, if an increase in Ca concentration over lO M takes place, e.g., due to cell damage, a level critical for the cell is reached. In this case, Ca is pumped into the mitochondria with the help of Ca transport systems localized in the iimer membrane of the mitochondrion. 

Fig. 7.19. Subunit structure and regulation of phosphorylase kinase of muscle. Phosphorylase kinase is - according to the excitation state of the muscle - regulated by two pathways. On nervous stimulation of the muscle, voltage-controlled Ca channels are opened, the cytosolic Ca concentration increases and Ca binds to calmoduhn, activating phosphorylase kinase. In resting muscle, activation of phosphorylase kinase is triggered by a hormonal signal. A hormonal signal initiates phosphorylation of the a and P subunits of phosphorylase kinase. In the phosphorylated form, Ca binding affinity of the calmodulin subunit (8) is strongly increased and activation is also possible at low Ca concentrations.

The sarcoplasmic reticulum is an organelle of muscle cells that resembles the ER in structure. It is used for rapid release and uptake of calcium ions. The resultant changes in cytosolic Ca " concentrations control muscle contraction,... 

The free Ca concentration in the extracellular fluid surrounding airway smooth muscle is approximately 1.5 mM, while cytosolic Ca " is below the micromolar range. The large electrochemical gradient across the plas-malemmal membrane results in a continuous passive leak of Ca into the cytosol. This leak of Ca into the cytosol is normally compensated for by the active Ca removal mechanisms (discussed later) which return Ca to the extracellular space, thereby preventing a rise in the cytosolic Ca concentration. 

Mitochondria are not involved in storing activator Ca in smooth muscle (Twort and van Breemen, 1989). Despite the importance of Ca transport systems within the mitochondria for controlling cellular metabolism, the endogenous Ca " content of mitochondria is low (Bond etal., 1984), and mitochondria in smooth muscle only accumulate Ca " at pathological (10 fiM) rather than physiological (100 nM) cytosolic Ca concentrations (Yamamoto and van Breemen, 1986). 

There are three main mechanisms for reducing cytosolic Ca concentration. These mechanisms maintain the concentration gradient of Ca " across the cell or sr membranes. Activation of these processes will reduce cytosolic Ca " and will produce relaxation (Fig. 9.5). 

In addition to this function of controlling the overall cytosolic Ca " concentration adjacent to the myofilaments in the deep cytosol, there is evidence that the st also plays a role in controlling the influx of extracellular Ca -" through the plasmalemmal membrane. This has led to the independent proposal of two concepts - the superficial buffer barrier hypothesis and the capacita-tive model - both of which attempt to link sr function to extracellular Ca " influx. 

McConkey, D.J., Nicotera, P., Hartzell, P., Bellomo, G., Wyllie, A.H. and Orrenius, S. (1989). Glucocorticoids activate a suicide process in thymocytes through an elevation of cytosolic Ca concentration. Arch. Biochem. Biophys. 269, 365-370. 

The inner mitochondrial membrane may function primarily as a calcium sink, taking up excess calcium in the cytosol that results from hormonal activation of the cell. At cytosolic Ca + concentrations greater than 0.6 /rmol/L, the mitochondrial calcium pump is activated and stores calcium in the mitochondrial matrix as a nonionic, rapidly exchangeable, phosphate salt. At low cytosolic calcium concentrations, the inner mitochondrial membrane allows Ca + to leak into the cytosol. The capacity of the active influx pathway (the pump) is much greater than that of the passive efflux route (the leak). The mitochondrial pump-leak system may serve to fine-tune the cytosolic calcium concentration while the plasma membrane is the principal safeguard against entry of toxic amounts of calcium into the cell. 

Most extracellular messengers that cause a rise in cytosolic Ca + concentration also increase the turnover... 

Calmodulin is a widely distributed cytosolic protein that contains four Ca -binding sites, one in each of its EF hands. Each EF hand has a helix-loop-helix motif At cytosolic Ca concentrations above about 5 X 10 M, binding of Ca to calmodulin changes the protein s conformation. The resulting Ca /calmodulin wraps around exposed helices of various target proteins, thereby altering their activity. 

The ionic gradients and electric potential across the plasma membrane play a role in many biological processes. As noted previously, a rise in the cytosolic Ca concentration is an Important regulatory signal. Initiating contraction in muscle cells and triggering secretion of digestive enzymes... 

Depolarization of the plasma membrane cannot, by itself, cause synaptic vesicles to fuse with the plasma membrane. In order to trigger vesicle fusion, an action potential must be converted Into a chemical signal—namely, a localized rise in the cytosolic Ca " concentration. The transducers of the electric signals are voltage-gated Ca channels localized to the region of the plasma membrane adjacent to the synaptic vesicles. The membrane depolarization due to arrival of an action potential opens these channels, permitting an influx... 

Like many cellular processes, skeletal muscle contraction Is Initiated by an Increase In the cytosolic Ca concentration. As described In Chapter 7, the Ca " concentration of the cytosol Is normally kept low, below 0.1 jjlM. In nonmuscle cells, Ca ATPases In the plasma membrane maintain this low concentration. In contrast. In skeletal muscle cells, a... 

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