Abstract
1. Na+ channel mRNA levels in the heart can be modulated by changes in intracellular Ca2+ ([Ca2+]i). We have investigated whether this regulation of Na+ channel biosynthesis by cytosolic Ca2+ translates into functional Na+ channels that can be detected electrophysiologically. 2. Whole-cell Na+ currents (INa) were recorded using patch-clamp techniques from single ventricular myocytes isolated from neonatal rats and maintained in tissue culture for 24 h. Na+ current density, measured at a membrane potential of -10 mV, was significantly decreased in the cells which were exposed for 24 h to culture medium containing 10 mM of both external Ca2+ and K+ in order to raise [Ca2+]i compared with control cells which were maintained in culture medium containing 2 and 5 mM of Ca2+ and K+, respectively. In contrast, Na+ current density (at -10 mV) was significantly increased in cells exposed for 24 h to 1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetra-acetic acid tetraacetoxymethyl ester (BAPTA AM; a cell membrane-permeable Ca2+ chelator) which lowered the average [Ca2+]i compared with control. 3. Changes in current density were not associated with changes in the voltage dependence of activation and inactivation of INa. There were no changes in single-channel conductances. 4. It is concluded that Na+ current density in neonatal rat cardiac myocytes is modulated by [Ca2+]i. The findings suggest that the differences in current density are attributable to a change in Na+ channel numbers rather than to changes in single-channel conductance or gating. These changes are consistent with the previously documented modulation of Na+ channel biosynthesis by cytosolic Ca2+.
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Selected References
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- Billman G. E., McIlroy B., Johnson J. D. Elevated myocardial calcium and its role in sudden cardiac death. FASEB J. 1991 Aug;5(11):2586–2592. doi: 10.1096/fasebj.5.11.1714409. [DOI] [PubMed] [Google Scholar]
- Cachelin A. B., De Peyer J. E., Kokubun S., Reuter H. Sodium channels in cultured cardiac cells. J Physiol. 1983 Jul;340:389–401. doi: 10.1113/jphysiol.1983.sp014768. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Cohen N. M., Lederer W. J. Calcium current in isolated neonatal rat ventricular myocytes. J Physiol. 1987 Oct;391:169–191. doi: 10.1113/jphysiol.1987.sp016732. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Duff H. J., Offord J., West J., Catterall W. A. Class I and IV antiarrhythmic drugs and cytosolic calcium regulate mRNA encoding the sodium channel alpha subunit in rat cardiac muscle. Mol Pharmacol. 1992 Oct;42(4):570–574. [PubMed] [Google Scholar]
- Field A. C., Hill C., Lamb G. D. Asymmetric charge movement and calcium currents in ventricular myocytes of neonatal rat. J Physiol. 1988 Dec;406:277–297. doi: 10.1113/jphysiol.1988.sp017380. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Furukawa T., Ito H., Nitta J., Tsujino M., Adachi S., Hiroe M., Marumo F., Sawanobori T., Hiraoka M. Endothelin-1 enhances calcium entry through T-type calcium channels in cultured neonatal rat ventricular myocytes. Circ Res. 1992 Nov;71(5):1242–1253. doi: 10.1161/01.res.71.5.1242. [DOI] [PubMed] [Google Scholar]
- Gillespie J. I., Meves H. The time course of sodium inactivation in squid giant axons. J Physiol. 1980 Feb;299:289–307. doi: 10.1113/jphysiol.1980.sp013125. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Grant A. O., Starmer C. F., Strauss H. C. Unitary sodium channels in isolated cardiac myocytes of rabbit. Circ Res. 1983 Dec;53(6):823–829. doi: 10.1161/01.res.53.6.823. [DOI] [PubMed] [Google Scholar]
- Grynkiewicz G., Poenie M., Tsien R. Y. A new generation of Ca2+ indicators with greatly improved fluorescence properties. J Biol Chem. 1985 Mar 25;260(6):3440–3450. [PubMed] [Google Scholar]
- Kilborn M. J., Fedida D. A study of the developmental changes in outward currents of rat ventricular myocytes. J Physiol. 1990 Nov;430:37–60. doi: 10.1113/jphysiol.1990.sp018280. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Klarsfeld A., Laufer R., Fontaine B., Devillers-Thiéry A., Dubreuil C., Changeux J. P. Regulation of muscle AChR alpha subunit gene expression by electrical activity: involvement of protein kinase C and Ca2+. Neuron. 1989 Mar;2(3):1229–1236. doi: 10.1016/0896-6273(89)90307-3. [DOI] [PubMed] [Google Scholar]
- Kunze D. L., Lacerda A. E., Wilson D. L., Brown A. M. Cardiac Na currents and the inactivating, reopening, and waiting properties of single cardiac Na channels. J Gen Physiol. 1985 Nov;86(5):691–719. doi: 10.1085/jgp.86.5.691. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Offord J., Catterall W. A. Electrical activity, cAMP, and cytosolic calcium regulate mRNA encoding sodium channel alpha subunits in rat muscle cells. Neuron. 1989 May;2(5):1447–1452. doi: 10.1016/0896-6273(89)90190-6. [DOI] [PubMed] [Google Scholar]
- Shainberg A., Freud-Silverberg M., Brik H. Changes in the levels of acetylcholine receptors mediated by calcium concentration in the sarcoplasmic reticulum. Prog Clin Biol Res. 1987;253:303–314. [PubMed] [Google Scholar]
- Sheets M. F., Scanley B. E., Hanck D. A., Makielski J. C., Fozzard H. A. Open sodium channel properties of single canine cardiac Purkinje cells. Biophys J. 1987 Jul;52(1):13–22. doi: 10.1016/S0006-3495(87)83183-1. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Sherman S. J., Catterall W. A. Electrical activity and cytosolic calcium regulate levels of tetrodotoxin-sensitive sodium channels in cultured rat muscle cells. Proc Natl Acad Sci U S A. 1984 Jan;81(1):262–266. doi: 10.1073/pnas.81.1.262. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Sherman S. J., Chrivia J., Catterall W. A. Cyclic adenosine 3':5'-monophosphate and cytosolic calcium exert opposing effects on biosynthesis of tetrodotoxin-sensitive sodium channels in rat muscle cells. J Neurosci. 1985 Jun;5(6):1570–1576. doi: 10.1523/JNEUROSCI.05-06-01570.1985. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Taouis M., Sheldon R. S., Duff H. J. Upregulation of the rat cardiac sodium channel by in vivo treatment with a class I antiarrhythmic drug. J Clin Invest. 1991 Aug;88(2):375–378. doi: 10.1172/JCI115313. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Tsien R. Y. A non-disruptive technique for loading calcium buffers and indicators into cells. Nature. 1981 Apr 9;290(5806):527–528. doi: 10.1038/290527a0. [DOI] [PubMed] [Google Scholar]
- Wendt D. J., Starmer C. F., Grant A. O. Na channel kinetics remain stable during perforated-patch recordings. Am J Physiol. 1992 Dec;263(6 Pt 1):C1234–C1240. doi: 10.1152/ajpcell.1992.263.6.C1234. [DOI] [PubMed] [Google Scholar]
- Williams D. A., Fogarty K. E., Tsien R. Y., Fay F. S. Calcium gradients in single smooth muscle cells revealed by the digital imaging microscope using Fura-2. Nature. 1985 Dec 12;318(6046):558–561. doi: 10.1038/318558a0. [DOI] [PubMed] [Google Scholar]