Electrogenic Na+/Ca2+-exchange of nerve and muscle cells
Introduction
The electrogenic and voltage-sensitive Na+/Ca2+-exchange was discovered nearly 40 years ago in nerve (Baker et al., 1967a, Baker et al., 1967b, Baker et al., 1969a, Baker and Blaustein, 1968) and muscle (Reuter and Seitz, 1967, Reuter and Seitz, 1968).
Earlier Lüttgau and Niedergerke (1958) had shown that a reduction of external Na+ ([Na+]o; Li+, choline+ or sucrose substitution) increased the contractility of frog ventricle in an external Ca2+-([Ca2+]o)-dependent manner and suggested a competition between the two ions for an extracellular binding site. They also suggested that the carrier (if any) is voltage-dependent. Indeed, flux measurements later demonstrated the interaction between [Na+]o and [Ca2+]o in frog ventricle muscle cells (Niedergerke, 1963).
The primary role of Na+/Ca2+-exchange is to extrude Ca2+ after excitation. For Ca2+-extrusion the energy of the Na+-gradient is required which is created by the Na+-pump. However, the exchanger can also work in reverse mode as well, i.e. internal Na+ ([Na+]i) can exchange for [Ca2+]o. Thus, if the Na+-pump is inhibited, the elevated level of Na+-inside may increase the influx of Ca2+ through the exchanger.
The Na+/Ca2+-exchange protein is expressed in many cells and during the past years several excellent reviews (Baker, 1972, Baker, 1986, Baker and Allen, 1984, Baker and Reuter, 1975, Blaustein, 1974, Blaustein, 1979, Blaustein, 1989, Requena and Mullins, 1979; Blaustein et al., 1991a, Blaustein et al., 1991b, Blaustein and Lederer, 1999, DiPolo and Beaugé, 1983, DiPolo and Beaugé, 1990, DiPolo and Beaugé, 1993, Philipson, 1985, Philipson, 1990, Philipson, 1999, Philipson, 2002, Philipson and Nicoll, 1992, Philipson and Nicoll, 1993, Philipson and Nicoll, 2000, Philipson et al., 1993, Reeves, 1985, Reeves, 1992, Reeves, 1998, Carafoli, 1985, Eisner and Lederer, 1985, Hilgemann, 1997, Khananshvilli, 1998, Schnetkamp, 1989, Lagnado and McNaughton, 1990, Bers, 2000, Annunziato et al., 2004, DiPolo and Beaugé, 2006) and Proceedings of International Conferences (Allen et al., 1989, Blaustein et al., 1991a, Hilgemann et al., 1996) have been published on Na+/Ca2+-exchange.
This current work concentrates mainly on the exchanger of nerve and muscle cells. Since the literature contains more than 2000 papers about Na+/Ca2+-exchange, I apologise to all of the authors whose significant and important work has not been cited here.
Section snippets
Stoichiometry and voltage-sensitivity of Na+/Ca2+-exchange
Table 1 summarizes the coupling-ratios of the exchanger published in the literature. In squid giant axons, a 3:1 stoichiometry has been determined by several laboratories (but see: Jundt et al., 1975). Cardiac muscle cells from different species, including dogs, rabbits, guinea-pigs, cows and rats also have a coupling ratio of 3:1 (but see: Ledvora and Hegyvary, 1983, Matsuoka, 2002, Dong et al., 2002) and, arterial smooth muscle cells, pancreatic beta-cells, barnacle muscle fibres and
Inward and outward Na+/Ca2+-exchange currents under physiological and pathological conditions
Since the exchanger is electrogenic, it generates a current through the membrane in the direction of the net charge carried by Na+. In normal mode of operation, it generates an inward current, thus it may prolong the duration of the AP. In reverse mode however, it produces an outward current, thereby repolarising the membrane and may shorten the duration of the AP. In this latter case however, the entering Ca2+ may produce activation of nerve and muscle cells in spite of the shortened AP.
Table 2
Number of Na+/Ca2+-exchange molecules (density of exchanger)
Since the Na+/Ca2+-exchanger and the Na+-pump are co-localised and functionally interact (see Section 9.1), it is worthwhile to make a comparison between them. The ATP-driven Ca2+-pump shows a uniform distribution in the plasma membrane and has a high affinity for Ca2+i (about 10 times higher to that of exchanger; DiPolo, 1979, Baker and DiPolo, 1984), but its turnover rate is relatively slow (around 50–150 s−1; Caroni and Carafoli, 1981, Schatzmann, 1983, Carafoli, 1983, Carafoli, 1987,
Turnover rate of Na+/Ca2+-exchange and other ion transporters
Most of the data published in the literature suggest that the Na+/Ca2+ exchanger has a much higher turnover rate than other membrane ion-extrusion transporters (e.g. Na+-pump: 80–200 Na+ s−1, Stein, 1986, Gadsby and Nakao, 1989, Friedrich et al., 1996; Ca2+-pump: ∼102 Ca2+ s−1, Stein, 1986).
Table 4 summarizes the values found in the literature.
In cardiac sarcolemmal vesicles Cheon and Reeves (1988) have determined a value around ∼1000 s−1 (see also: Reeves, 1989, Reeves, 1998).
Hilgemann et al.
Reversal potential (ENa/Ca) and driving force (ΔVNa/Ca) of Na+/Ca2+-exchange
The thermodynamic driving force for Na+/Ca2+-exchange can be expressed in terms of its reversal potential, i.e. the membrane potential at which the exchange system is in equilibrium:where ENa/Ca is the reversal potential, ENa and ECa are the equilibrium potentials for Na+ and Ca2+ determined by the Nernst equation, R the gas constant (8.314(1) J/kmol), T the absolute temperature (273 °C); (at 37 °C: 310 °C), and F the Faraday's constant
Pharmacology of Na+/Ca2+-exchange; putative inhibitors
The main problem for studying the physiological role of reverse Na+/Ca2+-exchange in “excitation-secretion/contraction coupling” is that no selective blocker is yet available (Siegl et al., 1984, Slaughter et al., 1988, Egger and Niggli, 1999; cf. Blaustein and Lederer, 1999). Mode-selective blockers (forward- and reverse-mode) are required. Currently used pharmacological tools will be described below.
Tetrodotoxin-sensitive Na+-influx-induced outward Na+/Ca2+-exchange current contributes to [Ca2+]i-transient and SR Ca2+-release (CICR) when ICa(L) is blocked
The data cited in this section differ, presumably depending on the species and the experimental conditions used. The fact that the exchanger, in comparison with other ion transporters, can readily reverse, supports the possibility that the reverse mode of operation may pertain under certain conditions in vivo. In fact, a crucial question is, the localisation of the Na+-channel and the Na+/Ca2+-exchanger. If Na+-channels are located close to the exchanger, the chance of exchanger mediated Ca2+
Na+-pump and Na+/Ca2+-exchange
The primary transporter, the Na+-pump is an electrogenic (3Na+:2K+) and voltage-sensitive ion transporter similar in these respects to the Na+/Ca2+-exchanger (cf. Baker, 1966, Baker and Connelly, 1966, Rang and Ritchie, 1968, Baker et al., 1969b, Kerkut and York, 1971, Thomas, 1972, Cavieres and Ellory, 1974, Glynn and Karlish, 1975, Akera, 1977, Akera and Brody, 1978, Glitsch, 1982, Glitsch, 2001, Hansen, 1984, De Weer, 1984, De Weer and Rakowski, 1984, Gadsby, 1984, Gadsby et al., 1985, Nakao
High voltage-activated Ca2+-channels involved in neurotransmitter release
Ca2+-entry through voltage-sensitive Ca2+-channels (VSCCs) triggers neurotransmitter release from presynaptic nerve terminals (Katz, 1969, Katz and Miledi, 1969, Nachshen and Blaustein, 1982, Augustine et al., 1985, Augustine et al., 1987, Augustine et al., 1991, Augustine and Charlton, 1986, Tsien et al., 1988, Almers, 1990, Mulkey and Zucker, 1991, Llinás et al., 1992, Randall and Tsien, 1995, Dunlap et al., 1995, Stanley, 1997, Bennett, 1999).
The “N-type” Ca2+-channel, first described in
Na+-pump and Na+/Ca2+-exchange regulation by adrenoceptors
Na+,K+-ATPase can be stimulated by catecholamines both in peripheral and central neurones (cf. Phillis and Wu, 1981).
In the heart, several studies have suggested that β-receptor activation can increase the activity of the Na+-pump (Wasserstrom et al., 1982, Lee and Vassalle, 1983, Désilets and Baumgarten, 1986, Sheu et al., 1991, Gao et al., 1992, Clausen, 1996, Overgaard et al., 1999). Other studies however, have failed to find evidence for stimulation (Glitsch et al., 1989, Ishizuka and
Conclusions
Selective blockers, even mode-selective blockers would be required to decide the physiological role of Na+/Ca2+-exchange in “excitation-secretion/contraction coupling”. In nerve terminals, e.g. in peripheral sympathetic nerves, the vesicle-docking sites and the exchanger proteins may localise close to each other. Since the nerve varicosities are so small, reverse Na+/Ca2+-exchange activation may occur physiologically, especially when AP frequency is high. Calculations based on the reversal
Acknowledgements
I thank Professor A.F. Brading (Department of Pharmacology, University of Oxford) for critical reading and discussion of the manuscript.
This work was supported, in part by The National Scientific Research Foundation (OTKA, Grant nos. 1020; T017749; TS040736; T042595), The Health Science Council (ETT, Grant nos. 237/96; 141/2003), Semmelweis University, (ETK-SOTE, Grant no. G6) and by a Grant from The Hungarian Academy of Sciences provided to the “Neurochemical Research Group of Semmelweis
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