Abstract
cAMP-dependent chloride channels in heart contribute to autonomic regulation of action potential duration and membrane potential and have been inferred to be due to cardiac expression of the epithelial cystic fibrosis transmembrane conductance regulator (CFTR) chloride channel. In this report, a cDNA from rabbit ventricle was isolated and sequenced, which encodes an exon 5 splice variant (exon 5-) of CFTR, with >90% identity to human CFTR cDNA present in epithelial cells. Expression of this cDNA in Xenopus oocytes gave rise to robust cAMP-activated chloride currents that were absent in control water-injected oocytes. Antisense oligodeoxynucleotides directed against CFTR significantly reduced the density of cAMP-dependent chloride currents in acutely cultured myocytes, thereby establishing a direct functional link between cardiac expression of CFTR protein and an endogenous chloride channel in native cardiac myocytes.
Full text
PDF





Images in this article
Selected References
These references are in PubMed. This may not be the complete list of references from this article.
- Ackerman M. J., Wickman K. D., Clapham D. E. Hypotonicity activates a native chloride current in Xenopus oocytes. J Gen Physiol. 1994 Feb;103(2):153–179. doi: 10.1085/jgp.103.2.153. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Bahinski A., Nairn A. C., Greengard P., Gadsby D. C. Chloride conductance regulated by cyclic AMP-dependent protein kinase in cardiac myocytes. Nature. 1989 Aug 31;340(6236):718–721. doi: 10.1038/340718a0. [DOI] [PubMed] [Google Scholar]
- Baukrowitz T., Hwang T. C., Nairn A. C., Gadsby D. C. Coupling of CFTR Cl- channel gating to an ATP hydrolysis cycle. Neuron. 1994 Mar;12(3):473–482. doi: 10.1016/0896-6273(94)90206-2. [DOI] [PubMed] [Google Scholar]
- Collier M. L., Hume J. R. Unitary chloride channels activated by protein kinase C in guinea pig ventricular myocytes. Circ Res. 1995 Feb;76(2):317–324. doi: 10.1161/01.res.76.2.317. [DOI] [PubMed] [Google Scholar]
- Delaney S. J., Rich D. P., Thomson S. A., Hargrave M. R., Lovelock P. K., Welsh M. J., Wainwright B. J. Cystic fibrosis transmembrane conductance regulator splice variants are not conserved and fail to produce chloride channels. Nat Genet. 1993 Aug;4(4):426–431. doi: 10.1038/ng0893-426. [DOI] [PubMed] [Google Scholar]
- Duan D. Y., Fermini B., Nattel S. Sustained outward current observed after I(to1) inactivation in rabbit atrial myocytes is a novel Cl- current. Am J Physiol. 1992 Dec;263(6 Pt 2):H1967–H1971. doi: 10.1152/ajpheart.1992.263.6.H1967. [DOI] [PubMed] [Google Scholar]
- Ehara T., Ishihara K. Anion channels activated by adrenaline in cardiac myocytes. Nature. 1990 Sep 20;347(6290):284–286. doi: 10.1038/347284a0. [DOI] [PubMed] [Google Scholar]
- Gadsby D. C., Nagel G., Hwang T. C. The CFTR chloride channel of mammalian heart. Annu Rev Physiol. 1995;57:387–416. doi: 10.1146/annurev.ph.57.030195.002131. [DOI] [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]
- Harvey R. D., Clark C. D., Hume J. R. Chloride current in mammalian cardiac myocytes. Novel mechanism for autonomic regulation of action potential duration and resting membrane potential. J Gen Physiol. 1990 Jun;95(6):1077–1102. doi: 10.1085/jgp.95.6.1077. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Harvey R. D., Hume J. R. Autonomic regulation of a chloride current in heart. Science. 1989 May 26;244(4907):983–985. doi: 10.1126/science.2543073. [DOI] [PubMed] [Google Scholar]
- Horowitz B., Tsung S. S., Hart P., Levesque P. C., Hume J. R. Alternative splicing of CFTR Cl- channels in heart. Am J Physiol. 1993 Jun;264(6 Pt 2):H2214–H2220. doi: 10.1152/ajpheart.1993.264.6.H2214. [DOI] [PubMed] [Google Scholar]
- Hume J. R., Horowitz B. A plethora of cardiac chloride conductances: molecular diversity or a related gene family. J Cardiovasc Electrophysiol. 1995 Apr;6(4):325–331. doi: 10.1111/j.1540-8167.1995.tb00404.x. [DOI] [PubMed] [Google Scholar]
- Hume J. R., Uehara A. Ionic basis of the different action potential configurations of single guinea-pig atrial and ventricular myocytes. J Physiol. 1985 Nov;368:525–544. doi: 10.1113/jphysiol.1985.sp015874. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Hwang T. C., Nagel G., Nairn A. C., Gadsby D. C. Regulation of the gating of cystic fibrosis transmembrane conductance regulator C1 channels by phosphorylation and ATP hydrolysis. Proc Natl Acad Sci U S A. 1994 May 24;91(11):4698–4702. doi: 10.1073/pnas.91.11.4698. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Kopelman H., Gauthier C., Bornstein M. Antisense oligodeoxynucleotide to the cystic fibrosis transmembrane conductance regulator inhibits cyclic AMP-activated but not calcium-activated cell volume reduction in a human pancreatic duct cell line. J Clin Invest. 1993 Mar;91(3):1253–1257. doi: 10.1172/JCI116289. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Kowdley G. C., Ackerman S. J., John J. E., 3rd, Jones L. R., Moorman J. R. Hyperpolarization-activated chloride currents in Xenopus oocytes. J Gen Physiol. 1994 Feb;103(2):217–230. doi: 10.1085/jgp.103.2.217. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Krauss R. D., Berta G., Rado T. A., Bubien J. K. Antisense oligonucleotides to CFTR confer a cystic fibrosis phenotype on B lymphocytes. Am J Physiol. 1992 Dec;263(6 Pt 1):C1147–C1151. doi: 10.1152/ajpcell.1992.263.6.C1147. [DOI] [PubMed] [Google Scholar]
- Krieg P. A., Melton D. A. Functional messenger RNAs are produced by SP6 in vitro transcription of cloned cDNAs. Nucleic Acids Res. 1984 Sep 25;12(18):7057–7070. doi: 10.1093/nar/12.18.7057. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Levesque P. C., Clark C. D., Zakarov S. I., Rosenshtraukh L. V., Hume J. R. Anion and cation modulation of the guinea-pig ventricular action potential during beta-adrenoceptor stimulation. Pflugers Arch. 1993 Jun;424(1):54–62. doi: 10.1007/BF00375102. [DOI] [PubMed] [Google Scholar]
- Levesque P. C., Hart P. J., Hume J. R., Kenyon J. L., Horowitz B. Expression of cystic fibrosis transmembrane regulator Cl- channels in heart. Circ Res. 1992 Oct;71(4):1002–1007. doi: 10.1161/01.res.71.4.1002. [DOI] [PubMed] [Google Scholar]
- Levesque P. C., Hume J. R. ATPo but not cAMPi activates a chloride conductance in mouse ventricular myocytes. Cardiovasc Res. 1995 Mar;29(3):336–343. [PubMed] [Google Scholar]
- Matsuura H., Ehara T. Activation of chloride current by purinergic stimulation in guinea pig heart cells. Circ Res. 1992 Apr;70(4):851–855. doi: 10.1161/01.res.70.4.851. [DOI] [PubMed] [Google Scholar]
- Moorman J. R., Palmer C. J., John J. E., 3rd, Durieux M. E., Jones L. R. Phospholemman expression induces a hyperpolarization-activated chloride current in Xenopus oocytes. J Biol Chem. 1992 Jul 25;267(21):14551–14554. [PubMed] [Google Scholar]
- Nagel G., Hwang T. C., Nastiuk K. L., Nairn A. C., Gadsby D. C. The protein kinase A-regulated cardiac Cl- channel resembles the cystic fibrosis transmembrane conductance regulator. Nature. 1992 Nov 5;360(6399):81–84. doi: 10.1038/360081a0. [DOI] [PubMed] [Google Scholar]
- Overholt J. L., Hobert M. E., Harvey R. D. On the mechanism of rectification of the isoproterenol-activated chloride current in guinea-pig ventricular myocytes. J Gen Physiol. 1993 Nov;102(5):871–895. doi: 10.1085/jgp.102.5.871. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Paulmichl M., Li Y., Wickman K., Ackerman M., Peralta E., Clapham D. New mammalian chloride channel identified by expression cloning. Nature. 1992 Mar 19;356(6366):238–241. doi: 10.1038/356238a0. [DOI] [PubMed] [Google Scholar]
- Rommens J. M., Iannuzzi M. C., Kerem B., Drumm M. L., Melmer G., Dean M., Rozmahel R., Cole J. L., Kennedy D., Hidaka N. Identification of the cystic fibrosis gene: chromosome walking and jumping. Science. 1989 Sep 8;245(4922):1059–1065. doi: 10.1126/science.2772657. [DOI] [PubMed] [Google Scholar]
- Sipido K. R., Callewaert G., Carmeliet E. [Ca2+]i transients and [Ca2+]i-dependent chloride current in single Purkinje cells from rabbit heart. J Physiol. 1993 Aug;468:641–667. doi: 10.1113/jphysiol.1993.sp019793. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Sorota S. Swelling-induced chloride-sensitive current in canine atrial cells revealed by whole-cell patch-clamp method. Circ Res. 1992 Apr;70(4):679–687. doi: 10.1161/01.res.70.4.679. [DOI] [PubMed] [Google Scholar]
- Sorscher E. J., Kirk K. L., Weaver M. L., Jilling T., Blalock J. E., LeBoeuf R. D. Antisense oligodeoxynucleotide to the cystic fibrosis gene inhibits anion transport in normal cultured sweat duct cells. Proc Natl Acad Sci U S A. 1991 Sep 1;88(17):7759–7762. doi: 10.1073/pnas.88.17.7759. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Thiemann A., Gründer S., Pusch M., Jentsch T. J. A chloride channel widely expressed in epithelial and non-epithelial cells. Nature. 1992 Mar 5;356(6364):57–60. doi: 10.1038/356057a0. [DOI] [PubMed] [Google Scholar]
- Tseng G. N. Cell swelling increases membrane conductance of canine cardiac cells: evidence for a volume-sensitive Cl channel. Am J Physiol. 1992 Apr;262(4 Pt 1):C1056–C1068. doi: 10.1152/ajpcell.1992.262.4.C1056. [DOI] [PubMed] [Google Scholar]
- Walsh K. B. Activation of a heart chloride current during stimulation of protein kinase C. Mol Pharmacol. 1991 Sep;40(3):342–346. [PubMed] [Google Scholar]
- Warth J. D., Collier M. L., Hart P., Geary Y., Gelband C. H., Chapman T., Horowitz B., Hume J. R. CFTR chloride channels in human and simian heart. Cardiovasc Res. 1996 Apr;31(4):615–624. [PubMed] [Google Scholar]
- Zhang K., Barrington P. L., Martin R. L., Ten Eick R. E. Protein kinase-dependent Cl- currents in feline ventricular myocytes. Circ Res. 1994 Jul;75(1):133–143. doi: 10.1161/01.res.75.1.133. [DOI] [PubMed] [Google Scholar]
- Zygmunt A. C., Gibbons W. R. Calcium-activated chloride current in rabbit ventricular myocytes. Circ Res. 1991 Feb;68(2):424–437. doi: 10.1161/01.res.68.2.424. [DOI] [PubMed] [Google Scholar]