Ca2 + /H+ exchange

Ca2+ pumps are needed for the removal of calcium from cells, as in the maintenance of low Ca2+ levels in resting muscle, in bone deposition, and in biomineralization. The Na+/Ca2+ exchanger and Ca2+-ATPase (a Ca2+/H+-exchanger) act in parallel to pump Ca2+ across membranes, the latter being considerably more effective than the former. X-ray structure determinations have been carried out both for Ca2+-ATPase and for its Ca2+-bound form (443). The latter contains two Ca2+ ions... 

Ca2+-transport ATPases [PMCA (Niggli et al., 1982) as well as SERCA (Martonosi et al., 1985)] operate as obligatory Ca2+-H+ exchangers. Since the number of protons exchanged for Ca + has not been firmly es-... 

Additional cellular events linked to the activity of blood pressure regulating substances involve membrane sodium transport mechanisms Na+/K.+ ATPase Na+fLi countertransport Na+ -H exchange Na+-Ca2+ exchange Na+-K+ 2C1 transport passive Na+ transport potassium channels cell volume and intracellular pH changes and calcium channels. 

Na+/Ca2+ Exchangers. Figure 5 Chemical structures of amiloride derivatives and their IC50 on NCX and NHX activity. Chemical structure of the two classes of amiloride derivatives and their inhibitory concentrations on NCX and Na+/H+ exchanger activity (Reproduced from Annunziato L, Pignataro G, Di Renzo GF (2004) Pharmacol Rev 56 633-654). 

Transduction mechanism Inhibition of adenylyl cyclase stimulation of tyrosine phosphatase activity stimulation of MAP kinase activity activation of ERK inhibition of Ca2+ channel activation stimulation of Na+/H+ exchanger stimulation of AM PA/kainate glutamate channels Inhibition of forskol in-stimulated adenylyl cyclase activation of phos-phoinositide metabolism stimulation of tyrosine phosphatase activity inhibition of Ca2+ channel activation activation of K+ channel inhibition of AM PA/ kainate glutamate channels inhibition of MAP kinase activity inhibition of ERK stimulation of SHP-1 and SHP-2 Inhibition of adenylyl cyclase stimulation of phosphoinositide metabolism stimulation of tyrosine phosphatase activation of K+ channel inhibi-tion/stimulation of MAP kinase activity induction of p53 and Bax Inhibition of adenylyl cyclase stimulation of MAP kinase stimulation of p38 activation of tyrosine phosphatase stimulation of K+ channels and phospholipase A2 Inhibition of adenylyl cyclase activation/ inhibition of phosphoinositide metabolism inhibition of Ca2+ influx activation of K+ channels inhibition of MAP kinase stimulation of tyrosine phosphatase... 

In transfected cells, H3 receptor mediated activation of Gj/0 proteins has also been reported to modulate arachi-donic acid release [29] and the Na+/H+ exchanger [44], and to inhibit Ca2+ influx and exocytosis of [3H] noradrenaline from transfected SH-SY5Y-H3 cells [45], The inhibition of Ca2+ influx may be particularly relevant in view of the known physiological function of the brain H3 receptor. 

Figure 1.3 Selective-binding sites in transport proteins for Na+, K+, Ca2+ and Cl. (a) Two Na+ binding sites in the LeuT Na+-dependent pump, (b) Four K+ binding sites in the KcsA K+ channel, (c) Two Ca2+ binding sites in the Ca2+ ATPase pump, (d) Two central Cl binding sites in a mutant C1C Cl /H+ exchanger. (From Gouax and MacKinnon, 2005. Copyright (2005) American Association for the Advancement of Science.)...

As described in the paragraphs above, conclusions on a direct effect of any of these ions should be drawn with caution, since a change in the concentration of any of these may activate a regulatory mechanism to compensate for the change, for example the Na+/H+ exchanger, the Na+/HCC>3 symport or the Na+/Ca2+-exchange mechanism. 

In addition to the Na+,K+- ATPases there is a very active Ca2+-ATPase which transports two Ca2+ from the inside of cells to the outside while returning two H+ from outside per ATP.510 543a This is the primary transporter by which cells maintain a low internal [Ca2+]. During its action it becomes phosphorylated on Asp 351. However, in neurons, in which the membrane potential is maintained at a high negative value by the sodium pump, an Na+/ Ca2+ ion exchange plays an even more important role.540... 

High-purity water for special applications is obtained by distillation or by ion exchange, the exchange of one type of ion in a solution by another. In ion exchange, water passes through a column packed with a material such as zeolite, an aluminosilicate with a very open structure that can capture ions such as Mg2+ and Ca2+ and exchange them for H+ ions (see Box 13.4). 

IP3 acts as the second messenger for Ca2+ mobilisation from the endoplasmic reticulum while DAG stimulates the Ca2+ sensitive protein kinase C (which modulates EGF receptor) and activates the plasma membrane Na+/H+ exchange carrier. In this function DAG is mimicked by phorbol esters which have a tumour promoting function. The effect of stimulating Na+/H+ exchange is to increase the intracellular pH and K+ concentration, conditions which are necessary to induce or maintain the proliferative response in quiescent cells (Rozengurt, 1986 Wakelam, 1989). 

Fig. 2 Schematic illustration of the possible role of K+ channels in [Ca2+]j, cell volume regulation and intracellular alkalization in tumor cells. Activation of K+ channels causes membrane hyperpolarization that in turn increases Ca2+ entry by increasing the driving force for Ca2+ and causes H+ extrusion by enhancing Na+/H+ exchanger activity leading to intracellular alkalization increased Ca2+ entry and intracellular alkalization induce Ca2+ release from Ca2+ store, leading to an increase in [Ca2+]i. Activation of K+ channels also causes H2O outflow due to hypotonic cytoplasm as a result of K+ efflux, leading to cell volume regulation...

In CHO cells, D4 receptors were shown to potentiate the increase in arachidonic acid release induced by ATP or Ca2+ ionophore. This effect appeared to require PTX-sensitive G proteins and to depend on PKC (Chio et al., 1994b Huff 1996). In the same cells, D4 receptor stimulation produced H+ excretion resulting from the activation of an amiloride-sensitive Na+/H+ exchanger through a PTX-sensitive mechanism (Chio et al., 1994b Coldwell et al., 1999). D4 receptor stimulation also increased the proliferation of CHO cells (Huff, 1996), showing that the signal transduction pathways stimulated by D4 receptors are identical to those stimulated by D2 receptors in this cell type. 

Using a variety of cell lines, D2R has been shown to couple to numerous G-proteins including Got i, Gai2, Gai3, Ga0 and Gaz. Depending on the cell type and isoform expressed, D2R activation can lead to the inhibition of AC and cAMP production, activation of potassium channels, inhibition of L-type calcium channels, stimulation of PLC activity and calcium mobilization, potentiation of Ca2+-evoked arachidonic acid release, stimulation of Na+/H+ exchange, and regulation of PI hydrolysis (Di Marzo et al., 1993 Mercier et al., 2001). 

Stimulation of oq-ARs results in the activation of various effectors, including PLC, phospholipase D (PLD), and phospholipase A2 (PLA2), as well as activation of Ca2+ channels and the Na+/H+ exchangers, modulation of K+ channels... 

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