Abstract
A single suction microelectrode voltage-clamp technique was used to study the actions of lanthanum ions (La3+) on ionic currents in single cells isolated from bullfrog right atrium. La3+, added as LaCl3, blocked the "slow" inward Ca2+ current (ICa) in a dose-dependent fashion; 10(-5) M produced complete inhibition. This effect was best fitted by a dose-response curve that was calculated assuming 1:1 binding of La3+ to a site having a dissociation constant of 7.5 x 10(- 7) M. La3+ block was reversed (to 90% of control ICa) following washout and, in the presence of 10(-5) M La3+, was antagonized by raising the Ca2+ concentration from 2.5 to 7.5 mM (ICa recovered to 56% of the control). However, the latter effect took approximately 1 h to develop. Concentrations of La3+ that reduced ICa by 12-67%, 0.1-1.5 x 10(-6) M, had no measurable effect upon the voltage dependence of steady state ICa inactivation, which suggest that at these concentrations there are no significant surface-charge effects of La3+ on this gating mechanism. Three additional findings indicate that doses of La3+ that blocked ICa failed to produce nonspecific effects: (a) 10(-5) M La3+ had no measurable effect on the time-independent inwardly rectifying current, IK1; (b) the same concentration had no effect on the kinetics, amplitude, or voltage dependence of a time- and voltage-dependent K+ current, IK; and (c) 10(-4) M La3+ did not alter the size of the tetrodotoxin-sensitive inward Na+ current, INa, or the voltage dependence of its steady state inactivation. Higher concentrations (0.5- 1.0 mM) reduced both IK1 and IK, and shifted the steady state activation curve for IK toward more positive potentials, presumably by reducing the external surface potential. Our results suggest that at a concentration of less than or equal to 10(-5) M, La3+ inhibits ICa selectively by direct blockade of Ca channels rather than by altering the external surface potential. At higher concentrations, La3+ exhibits nonspecific effects, including neutralization of negative external surface charge and inhibition of other time- and voltage-dependent ionic currents.
Full Text
The Full Text of this article is available as a PDF (1.3 MB).
Selected References
These references are in PubMed. This may not be the complete list of references from this article.
- Akaike N., Lee K. S., Brown A. M. The calcium current of Helix neuron. J Gen Physiol. 1978 May;71(5):509–531. doi: 10.1085/jgp.71.5.509. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Anderson N. C., Ramon F., Snyder A. Studies on calcium and sodium in uterine smooth muscle excitation under current-clamp and voltage-clamp conditions. J Gen Physiol. 1971 Sep;58(3):322–339. doi: 10.1085/jgp.58.3.322. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Baker P. F., Meves H., Ridgway E. B. Effects of manganese and other agents on the calcium uptake that follows depolarization of squid axons. J Physiol. 1973 Jun;231(3):511–526. doi: 10.1113/jphysiol.1973.sp010246. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Barry W. H., Goldminz D., Kimball T., Fitzgerald J. W. Influence of cell dissociation and culture of chick embryo ventricle on inotropic responses to calcium and lanthanum. J Mol Cell Cardiol. 1978 Oct;10(10):967–979. doi: 10.1016/0022-2828(78)90342-5. [DOI] [PubMed] [Google Scholar]
- Begenisich T. Magnitude and location of surface charges on Myxicola giant axons. J Gen Physiol. 1975 Jul;66(1):47–65. doi: 10.1085/jgp.66.1.47. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Belardinelli L., Rubio R., Berne R. M. Blockade of Ca2+ dependent rat atrial slow action potentials by adenosine and lanthanum. Pflugers Arch. 1979 May 15;380(1):19–27. doi: 10.1007/BF00582607. [DOI] [PubMed] [Google Scholar]
- Blaustein M. P., Goldman D. E. The action of certain polyvalent cations on the voltage-clamped lobster axon. J Gen Physiol. 1968 Mar;51(3):279–291. doi: 10.1085/jgp.51.3.279. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Bockman E. L., Rubio R., Berne R. M. Effect of lanthanum on isoproterenol-induced activation of myocardial phosphorylase. Am J Physiol. 1973 Aug;225(2):438–443. doi: 10.1152/ajplegacy.1973.225.2.438. [DOI] [PubMed] [Google Scholar]
- Brismar T. The effect of divalent and trivalent cations on the sodium permeability of myelinated nerve fibres of Xenopus laevis. Acta Physiol Scand. 1980 Jan;108(1):23–29. doi: 10.1111/j.1748-1716.1980.tb06496.x. [DOI] [PubMed] [Google Scholar]
- Brown R. H., Jr Membrane surface charge: discrete and uniform modelling. Prog Biophys Mol Biol. 1974;28:341–370. doi: 10.1016/0079-6107(74)90021-2. [DOI] [PubMed] [Google Scholar]
- Carmeliet E. Repolarisation and frequency in cardiac cells. J Physiol (Paris) 1977;73(7):903–923. [PubMed] [Google Scholar]
- Chapman R. A., Tunstall J. The interaction of sodium and calcium ions at the cell membrane and the control of contractile strength in frog atrial muscle. J Physiol. 1980 Aug;305:109–123. doi: 10.1113/jphysiol.1980.sp013353. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Clark R. B., Giles W. Sodium current in single cells from bullfrog atrium: voltage dependence and ion transfer properties. J Physiol. 1987 Oct;391:235–265. doi: 10.1113/jphysiol.1987.sp016736. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Croaboeuf E., Gautier P., Giuraudou P. Potential and tension changes induced by sodium removal in dog Purkinje fibres: role of an electrogenic sodium-calcium exchange. J Physiol. 1981 Feb;311:605–622. doi: 10.1113/jphysiol.1981.sp013607. [DOI] [PMC free article] [PubMed] [Google Scholar]
- De Hemptinne A. The frequency dependence of outward current in frog auricular fibres. An experimental and theoretical study. Pflugers Arch. 1971;329(4):332–340. doi: 10.1007/BF00588004. [DOI] [PubMed] [Google Scholar]
- Dörrscheidt-Käfer M. Comparison of the action of La3+ and Ca2+ on contraction threshold and other membrane parameters of frog skeletal muscle. J Membr Biol. 1981;62(1-2):95–103. doi: 10.1007/BF01870203. [DOI] [PubMed] [Google Scholar]
- FRANKENHAEUSER B., HODGKIN A. L. The action of calcium on the electrical properties of squid axons. J Physiol. 1957 Jul 11;137(2):218–244. doi: 10.1113/jphysiol.1957.sp005808. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Gilly W. F., Armstrong C. M. Divalent cations and the activation kinetics of potassium channels in squid giant axons. J Gen Physiol. 1982 Jun;79(6):965–996. doi: 10.1085/jgp.79.6.965. [DOI] [PMC free article] [PubMed] [Google Scholar]
- HODGKIN A. L., HUXLEY A. F. A quantitative description of membrane current and its application to conduction and excitation in nerve. J Physiol. 1952 Aug;117(4):500–544. doi: 10.1113/jphysiol.1952.sp004764. [DOI] [PMC free article] [PubMed] [Google Scholar]
- HODGKIN A. L., HUXLEY A. F. The dual effect of membrane potential on sodium conductance in the giant axon of Loligo. J Physiol. 1952 Apr;116(4):497–506. doi: 10.1113/jphysiol.1952.sp004719. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Haass A. Effects of lanthanum, calcium and barium on the resting membrane resistance of guinea-pig papillary muscles. Naunyn Schmiedebergs Arch Pharmacol. 1975;290(2-3):207–220. doi: 10.1007/BF00510551. [DOI] [PubMed] [Google Scholar]
- Hagiwara S. Ca-dependent action potential. Membranes. 1975;3:359–381. [PubMed] [Google Scholar]
- Hamill O. P., Marty A., Neher E., Sakmann B., Sigworth F. J. Improved patch-clamp techniques for high-resolution current recording from cells and cell-free membrane patches. Pflugers Arch. 1981 Aug;391(2):85–100. doi: 10.1007/BF00656997. [DOI] [PubMed] [Google Scholar]
- Hatae J. Effects of lanthanum on the electrical and mechanical activities of frog ventricular muscle. Jpn J Physiol. 1982;32(4):609–625. doi: 10.2170/jjphysiol.32.609. [DOI] [PubMed] [Google Scholar]
- Henkart M., Hagiwara S. Localization of calcium binding sites associated with the calcium spike in barnacle muscle. J Membr Biol. 1976 Jun 9;27(1-2):1–20. doi: 10.1007/BF01869126. [DOI] [PubMed] [Google Scholar]
- Hille B., Woodhull A. M., Shapiro B. I. Negative surface charge near sodium channels of nerve: divalent ions, monovalent ions, and pH. Philos Trans R Soc Lond B Biol Sci. 1975 Jun 10;270(908):301–318. doi: 10.1098/rstb.1975.0011. [DOI] [PubMed] [Google Scholar]
- Horackova M., Vassort G. Sodium-calcium exchange in regulation of cardiac contractility. Evidence for an electrogenic, voltage-dependent mechanism. J Gen Physiol. 1979 Apr;73(4):403–424. doi: 10.1085/jgp.73.4.403. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Hume J. R. Comparative interactions of organic Ca++ channel antagonists with myocardial Ca++ and K+ channels. J Pharmacol Exp Ther. 1985 Jul;234(1):134–140. [PubMed] [Google Scholar]
- Hume J. R., Giles W. Active and passive electrical properties of single bullfrog atrial cells. J Gen Physiol. 1981 Jul;78(1):19–42. doi: 10.1085/jgp.78.1.19. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Hume J. R., Giles W. Ionic currents in single isolated bullfrog atrial cells. J Gen Physiol. 1983 Feb;81(2):153–194. doi: 10.1085/jgp.81.2.153. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Hume J. R., Giles W., Robinson K., Shibata E. F., Nathan R. D., Kanai K., Rasmusson R. A time- and voltage-dependent K+ current in single cardiac cells from bullfrog atrium. J Gen Physiol. 1986 Dec;88(6):777–798. doi: 10.1085/jgp.88.6.777. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Hume J. R., Uehara A. Properties of "creep currents" in single frog atrial cells. J Gen Physiol. 1986 Jun;87(6):833–855. doi: 10.1085/jgp.87.6.833. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Isenberg G., Klöckner U. Calcium currents of isolated bovine ventricular myocytes are fast and of large amplitude. Pflugers Arch. 1982 Oct;395(1):30–41. doi: 10.1007/BF00584965. [DOI] [PubMed] [Google Scholar]
- Isenberg G., Klöckner U. Glycocalyx is not required for show inward calcium current in isolated rat heart myocytes. Nature. 1980 Mar 27;284(5754):358–360. doi: 10.1038/284358a0. [DOI] [PubMed] [Google Scholar]
- Jacob R., Lieberman M., Liu S. Electrogenic sodium-calcium exchange in cultured embryonic chick heart cells. J Physiol. 1987 Jun;387:567–588. doi: 10.1113/jphysiol.1987.sp016589. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Kass R. S., Krafte D. S. Negative surface charge density near heart calcium channels. Relevance to block by dihydropyridines. J Gen Physiol. 1987 Apr;89(4):629–644. doi: 10.1085/jgp.89.4.629. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Kass R. S. Nisoldipine: a new, more selective calcium current blocker in cardiac Purkinje fibers. J Pharmacol Exp Ther. 1982 Nov;223(2):446–456. [PubMed] [Google Scholar]
- Kass R. S., Tsien R. W. Multiple effects of calcium antagonists on plateau currents in cardiac Purkinje fibers. J Gen Physiol. 1975 Aug;66(2):169–192. doi: 10.1085/jgp.66.2.169. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Katzung B. G., Reuter H., Porzig H. Lanthanum inhibits Ca inward current but not Na-Ca exchange in cardiac muscle. Experientia. 1973 Sep 15;29(9):1073–1075. doi: 10.1007/BF01946727. [DOI] [PubMed] [Google Scholar]
- Kimura J., Miyamae S., Noma A. Identification of sodium-calcium exchange current in single ventricular cells of guinea-pig. J Physiol. 1987 Mar;384:199–222. doi: 10.1113/jphysiol.1987.sp016450. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Langer G. A., Frank J. S. Lanthanum in heart cell culture. Effect on calcium exchange correlated with its localization. J Cell Biol. 1972 Sep;54(3):441–455. doi: 10.1083/jcb.54.3.441. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Lansman J. B., Hess P., Tsien R. W. Blockade of current through single calcium channels by Cd2+, Mg2+, and Ca2+. Voltage and concentration dependence of calcium entry into the pore. J Gen Physiol. 1986 Sep;88(3):321–347. doi: 10.1085/jgp.88.3.321. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Lee K. S., Tsien R. W. Reversal of current through calcium channels in dialysed single heart cells. Nature. 1982 Jun 10;297(5866):498–501. doi: 10.1038/297498a0. [DOI] [PubMed] [Google Scholar]
- Martinez-Palomo A., Benitez D., Alanis J. Selective deposition of lanthanum in mammalian cardiac cell membranes. Ultrastructural and electrophysiological evidence. J Cell Biol. 1973 Jul;58(1):1–10. doi: 10.1083/jcb.58.1.1. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Matteson D. R., Armstrong C. M. Na and Ca channels in a transformed line of anterior pituitary cells. J Gen Physiol. 1984 Mar;83(3):371–394. doi: 10.1085/jgp.83.3.371. [DOI] [PMC free article] [PubMed] [Google Scholar]
- McLaughlin S. G., Szabo G., Eisenman G. Divalent ions and the surface potential of charged phospholipid membranes. J Gen Physiol. 1971 Dec;58(6):667–687. doi: 10.1085/jgp.58.6.667. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Mechmann S., Pott L. Identification of Na-Ca exchange current in single cardiac myocytes. Nature. 1986 Feb 13;319(6054):597–599. doi: 10.1038/319597a0. [DOI] [PubMed] [Google Scholar]
- Mentrard D., Vassort G., Fischmeister R. Changes in external Na induce a membrane current related to the Na-Ca exchange in cesium-loaded frog heart cells. J Gen Physiol. 1984 Aug;84(2):201–220. doi: 10.1085/jgp.84.2.201. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Meyer R., Schmitz M., Stockem W., Haas H. G. Localization of Ca2+ at the plasma membrane of bullfrog myocardial cells. Z Naturforsch C. 1982 Nov-Dec;37(11-12):1180–1190. doi: 10.1515/znc-1982-11-1221. [DOI] [PubMed] [Google Scholar]
- Meyer R., Stockem W., Schmitz M., Haas H. G. Histochemical demonstration of an ATP-dependent Ca2+-pump in bullfrog myocardial cells. Z Naturforsch C. 1982 May-Jun;37(5-6):489–501. doi: 10.1515/znc-1982-5-622. [DOI] [PubMed] [Google Scholar]
- Miller D. J., Mörchen A. On the effects of divalent cations and ethylene glycol-bis-(beta-aminoethyl ether) N,N,N',N'-tetraacetate on action potential duration in frog heart. J Gen Physiol. 1978 Jan;71(1):47–67. doi: 10.1085/jgp.71.1.47. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Mines G. R. The action of beryllium, lanthanum, yttrium and cerium on the frog's heart. J Physiol. 1910 May 13;40(4):327–346. doi: 10.1113/jphysiol.1910.sp001373. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Moolenaar W. H., Spector I. The calcium current and the activation of a slow potassium conductance in voltage-clamped mouse neuroblastoma cells. J Physiol. 1979 Jul;292:307–323. doi: 10.1113/jphysiol.1979.sp012852. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Mullins L. J. A mechanism for Na/Ca transport. J Gen Physiol. 1977 Dec;70(6):681–695. doi: 10.1085/jgp.70.6.681. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Nachshen D. A. Selectivity of the Ca binding site in synaptosome Ca channels. Inhibition of Ca influx by multivalent metal cations. J Gen Physiol. 1984 Jun;83(6):941–967. doi: 10.1085/jgp.83.6.941. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Nayler W. G., Harris J. P. Inhibition by Lanthanum of the Na+ + K+ activated, ouabain-sensitive adenosinetriphosphatase enzyme. J Mol Cell Cardiol. 1976 Oct;8(10):811–822. doi: 10.1016/0022-2828(76)90087-0. [DOI] [PubMed] [Google Scholar]
- Neumcke B., Stämpfli R. Heterogeneity of external surface charges near sodium channels in the nodal membrane of frog nerve. Pflugers Arch. 1984 Jun;401(2):125–131. doi: 10.1007/BF00583872. [DOI] [PubMed] [Google Scholar]
- Noble S., Shimoni Y. The calcium and frequency dependence of the slow inward current 'staircase' in frog atrium. J Physiol. 1981 Jan;310:57–75. doi: 10.1113/jphysiol.1981.sp013537. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Ohmori H., Yoshii M. Surface potential reflected in both gating and permeation mechanisms of sodium and calcium channels of the tunicate egg cell membrane. J Physiol. 1977 May;267(2):429–463. doi: 10.1113/jphysiol.1977.sp011821. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Pressler M. L., Elharrar V., Bailey J. C. Effects of extracellular calcium ions, verapamil, and lanthanum on active and passive properties of canine cardiac purkinje fibers. Circ Res. 1982 Nov;51(5):637–651. doi: 10.1161/01.res.51.5.637. [DOI] [PubMed] [Google Scholar]
- Provencher S. W. A Fourier method for the analysis of exponential decay curves. Biophys J. 1976 Jan;16(1):27–41. doi: 10.1016/S0006-3495(76)85660-3. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Ravens U. The effects of lanthanum on electrical and mechanical events in mammalian cardiac muscle. Naunyn Schmiedebergs Arch Pharmacol. 1975;288(2-3):133–146. doi: 10.1007/BF00500521. [DOI] [PubMed] [Google Scholar]
- Reeves J. P., Sutko J. L. Sodium-calcium ion exchange in cardiac membrane vesicles. Proc Natl Acad Sci U S A. 1979 Feb;76(2):590–594. doi: 10.1073/pnas.76.2.590. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Reuter H. Divalent cations as charge carriers in excitable membranes. Prog Biophys Mol Biol. 1973;26:1–43. doi: 10.1016/0079-6107(73)90016-3. [DOI] [PubMed] [Google Scholar]
- Reuter H., Scholz H. A study of the ion selectivity and the kinetic properties of the calcium dependent slow inward current in mammalian cardiac muscle. J Physiol. 1977 Jan;264(1):17–47. doi: 10.1113/jphysiol.1977.sp011656. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Sanborn W. G., Langer G. A. Specific uncoupling of excitation and contraction in mammalian cardiac tissue by lanthanum. J Gen Physiol. 1970 Aug;56(2):191–217. doi: 10.1085/jgp.56.2.191. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Siegelbaum S. A., Tsien R. W., Kass R. S. Role of intracellular calcium in the transient outward current of calf Purkinje fibres. Nature. 1977 Oct 13;269(5629):611–613. doi: 10.1038/269611a0. [DOI] [PubMed] [Google Scholar]
- Takata M., Pickard W. F., Lettvin J. Y., Moore J. W. Ionic conductance changes in lobster axon membrane when lanthanum is substituted for calcium. J Gen Physiol. 1966 Nov;50(2):461–471. doi: 10.1085/jgp.50.2.461. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Takeo S., Duke P., Taam G. M., Singal P. K., Dhalla N. S. Effects of lanthanum on the heart sarcolemmal ATPase and calcium binding activities. Can J Physiol Pharmacol. 1979 May;57(5):496–503. doi: 10.1139/y79-075. [DOI] [PubMed] [Google Scholar]
- Trautwein W., McDonald T. F., Tripathi O. Calcium conductance and tension in mammalian ventricular muscle. Pflugers Arch. 1975;354(1):55–74. doi: 10.1007/BF00584503. [DOI] [PubMed] [Google Scholar]
- Trosper T. L., Philipson K. D. Effects of divalent and trivalent cations on Na+-Ca2+ exchange in cardiac sarcolemmal vesicles. Biochim Biophys Acta. 1983 May 26;731(1):63–68. doi: 10.1016/0005-2736(83)90398-x. [DOI] [PubMed] [Google Scholar]
- Tsien R. W. Calcium channels in excitable cell membranes. Annu Rev Physiol. 1983;45:341–358. doi: 10.1146/annurev.ph.45.030183.002013. [DOI] [PubMed] [Google Scholar]
- Tsien R. W. Effects of epinephrine on the pacemaker potassium current of cardiac Purkinje fibers. J Gen Physiol. 1974 Sep;64(3):293–319. doi: 10.1085/jgp.64.3.293. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Tsien R. W. Mode of action of chronotropic agents in cardiac Purkinje fibers. Does epinephrine act by directly modifying the external surface charge? J Gen Physiol. 1974 Sep;64(3):320–342. doi: 10.1085/jgp.64.3.320. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Urata M., Goto M. Membrane currents related to configuration changes in the action potential of frog atrial muscle in Na- and Ca-free conditions. J Mol Cell Cardiol. 1982 Jul;14(7):371–379. doi: 10.1016/0022-2828(82)90169-9. [DOI] [PubMed] [Google Scholar]
- Vogel W. Calcium and lanthanum effects at the nodal membrane. Pflugers Arch. 1974;350(1):25–39. doi: 10.1007/BF00586736. [DOI] [PubMed] [Google Scholar]
- Walker J. L., Ladle R. O. Frog heart intracellular potassium activities measured with potassium microelectrodes. Am J Physiol. 1973 Jul;225(1):263–267. doi: 10.1152/ajplegacy.1973.225.1.263. [DOI] [PubMed] [Google Scholar]
- Wendt-Gallitelli M. F., Isenberg G. Extra- and intracellular lanthanum: modified calcium distribution, inward currents and contractility in guinea pig ventricular preparations. Pflugers Arch. 1985 Dec;405(4):310–322. doi: 10.1007/BF00595683. [DOI] [PubMed] [Google Scholar]
- Wilson D. L., Morimoto K., Tsuda Y., Brown A. M. Interaction between calcium ions and surface charge as it relates to calcium currents. J Membr Biol. 1983;72(1-2):117–130. doi: 10.1007/BF01870319. [DOI] [PubMed] [Google Scholar]
- Yau K. W., Nakatani K. Electrogenic Na-Ca exchange in retinal rod outer segment. Nature. 1984 Oct 18;311(5987):661–663. doi: 10.1038/311661a0. [DOI] [PubMed] [Google Scholar]