Na+/Ca + antiporters

Figure 6.8. Digitalis (foxglove) glycosides, a Mode of action. The drags inhibit the Na /K -ATP ase. The increased intracellular sodium concentration will reduce the activity of the Na /Ca antiport system and therefore lead to an increase of intracellular Ca and augment myofilament contraction, b Structures.

Calcium may also be taken up by Na -Ca exchange. Thus sperm plasma membranes take up Ca by an ATP-independent Na /Ca antiporter. Ejaculated sperm cannot do this, due to the presence of a protein" that binds strongly to the plasma membrane. A highly active, electrogenic Na" /Ca exchange occurs in sarcolemmal vesicles from cardiac muscle. ... 

The basal lateral plasma membrane contains at least two types of Ca + pumps that also may play a role in Ca " " uptake, one ATP-driven, one driven by a concurrent flow of Na" " ions into the cytoplasm (i.e., a Na -Ca + antiport see Figure 3.8). We discuss these types of transporting proteins in the next subsection. 

Lanthanum can enter (bovine) chromaffin cells via the Na/Ca antiporter independently of, or together with, Ca but, high concentrations of La block the influx or efflux of Ca. La is at least as effective as Ca in triggering catecholamine release and maintaining prolonged release, and acts cooperatively with Ca at the release pathway (Powis, Clark et al. 1994). 

The levels of these second messengers rise transiently in response to the primary signalling molecules (Hs or NTs) binding to their specific receptors. Thus Ca is pumped out of the cell by plasma membrane Ca -ATPases or by Na+/Ca2+ antiporters which utilize the Na+ gradient... 

Protein kinase C activation has been implicated in augmenting the transmembrane flux of calcium ions, the activities of the Na K -ATPase, as well as the activity of the Na /H -antiporter. Substantial evidence suggests that protein kinase C augments the uptake of calcium released during cellular stimulation, thereby limiting the temporal duration of its activation (e.g., phorbol esters activate the sarcoplasmic reticulum Ca -ATPase). 

In cardiac muscle cells a three-Na /one-Ca antiporter, rather than the plasma membrane Ca ATPase discussed earlier, plays the principal role in maintaining a low concentration of Ca in the cytosol. The transport reaction mediated by this cation antiporter can be written... 

Uptake of sucrose, Na, Ca ", and other substances into plant vacuoles is carried out by proton antiporters in the vacuolar membrane. Ion channels and proton pumps in the membrane are critical in generating a large enough proton concentration gradient to power accumulation of ions and metabolites in vacuoles by these proton antiporters (see Figure 7-23). 

Fig. 4.22. Hypoxia-mediated metabolic adaptation for energy preservation. Activation of genes for glucose transporter-1 (GLUT-1 = 1) and glycolytic enzymes yields an increased glycolytic rate. H -ions produced are preferentially exported via a Na /H -antiporter (NHE-1 = 3) and a lactate /H -symporter (monocarboxylate transporter MCT-1 = 2) leading to a drop in extracellular pH (pH.). Low extracellular pH activates the membrane-bound ectoenzyme carbonic anhydrase IX (CA IX = 4). Key mechanism regulating intracellular pH in tumor cells when protons are produced is also shown (Na -depen-dent HCOs" /CL -exchanger = 5). HIF-Ia = hypoxia-inducible factor la, PHDs = prolyl hydroxylases, FIH = asparagyl hydroxylase, lac" = lactic acid...

The molecular mechanisms by which growth factors exert their influence remain largely unknown. However, on growth factor-receptor interaction, the intrinsic kinase activity catalyses the phosphorylation of target cytoplasmic proteins only on tyrosyl residues. These tyrosine-specific protein phosphorylations may initiate a cascade of biochemical events which ultimately promote DNA synthesis and cell division. Other consequences of the binding of growth factors to their receptors include the hydrolysis of phosphoinositides, a sustained rise in cytoplasmic pH through the activation of an Na /H antiport mechanism in the plasma membrane and a transient rise in cytoplasmic free Ca concentration. However, EGF-... 

The Ca H or Na cation antiporters (CaCA family) (Lytton 2007) are similarly represented in actinobacteria. Gram (-) bacteria, and archaea, but non-LAB firmicutes have substantially reduced numbers, and LAB lack these carriers altogether. These porters function primarily to exclude cytoplasmic Ca, but some of them can also export other divalent ions. In the next section we shall... 

Transport systems can be described in a functional sense according to the number of molecules moved and the direction of movement (Figure 41-10) or according to whether movement is toward or away from equilibrium. A uniport system moves one type of molecule bidirectionally. In cotransport systems, the transfer of one solute depends upon the stoichiometric simultaneous or sequential transfer of another solute. A symport moves these solutes in the same direction. Examples are the proton-sugar transporter in bacteria and the Na+ -sugar transporters (for glucose and certain other sugars) and Na -amino acid transporters in mammalian cells. Antiport systems move two molecules in opposite directions (eg, Na in and Ca out). 

Figure 12.2 Mechanism of action of carbonic anhydrase inhibitors on the proximai convoiuted tubuie. Carbonic anhydrase is an enzyme that cataiyses the interconversion of C02and H20 to H2C03and is found in the iuminai epitheiium of the proximai, and to a iesser extent, the distai convoiuted tubuie. It is essentiai for the conservation of body base in the form of HCO-3. An antiporter (1) mechanism (the movement of substances across a barrier in opposite directions) exchanges fiitrate Na+for ceiiuiar H+. The H+combines with fiitrate HCO-3to form carbonic acid which is converted to C02and H20 in the presence of carbonic anhydrase (CA). The C02is reabsorbed by the ceii thereby conserving HCO-3. Acetazoiamide inhibits the activity of carbonic anhydrase and limits the conversion of HCO-3to absorbable C02. The concentration of HCO-3in the filtrate increases as does the urinary loss. P, the sodium pump ECF, extracellular fluid.

Analogous to the treatment of the antiporter in Section 7.1.2, the mechanism of Figure 7.5 assumes that the binding and unbinding steps are lumped into single reactions. This assumption is reasonable if the binding and unbinding reaction are maintained in rapid equilibrium ex = [Na+J3[Ca2+]< i/A / and e- = [Na+]3[Ca ]e4/A. These relationships allow us to simplify Equation (7.23) to... 

The ATPase has an absolute requirement for Mg " which is essential for the breakdown of the phosphorylated intermediate. There is evidence for at least three forms of the phosphoenzyme, only the last of which is sensitive to Mg . " " Monovalent cations are effective as activators in the sequence Tl > Na " > NH4 > Rb Cs > Li, again through the promotion of the loss of phosphate from the phosphorylated intermediate. It has been postulated that K may be involved in antiport with Ca " to maintain charge balance, but it is currently thought that this involves protons or a flux of anions. 

Thus, at least four different mechanisms have been established for the exclusion of Ca by bacterial cells, namely, active efflux of Ca via the Cd lW antiport ( . coli, Azotobacter vtnelandii and Mycobacterium phlei), the Ca /Na antiport H. halobium), via the hydrolysis of ATP (S. faecalis), and calcium-phosphate symport ( . coli). 

Normally Na+ brought in by the Na/Cl cotransporter is exchanged for K+ via the pump on the basolateral membrane, K+ returning to the blood by back-diffusion. Cl ions return to the blood via diffusion through special channels. Ca2+ diffuses across the luminal membrane through channels regulated by PTH and is returned to the blood by a Ca/Na antiporter. 

Inhibition of the Na/Cl cotransporter increases the luminal concentrations of these ions. Hypokalemia and alkalosis occur consequent to the Na+ load downstream. Increased activity of the Ca/Na antiporter (regulated by PTH) leads to increased reabsorption of Ca2+ —> possible hypercalcemia. 

In cardiac muscle cells, the export of Ca Is coupled to and powered by the import of Na by a cation antiporter, which transports 3 Na ions inward for each Ca Ion exported. 

Mitochondria, as well as SR, release Ca + ions by mechanisms other than back leakage through the pumps. In mitochondria from excitable cells, the efflux occurs mainly through an antiport, where 2 Na+ ions are transported inward for every Ca ion departing for the cytosolic compartment. In other cells there is evidence for the dominance of a 2H" antiport.In all... 

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