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. 1999 May 4;18(9):2323–2329. doi: 10.1093/emboj/18.9.2323

Two pacemaker channels from human heart with profoundly different activation kinetics.

A Ludwig 1, X Zong 1, J Stieber 1, R Hullin 1, F Hofmann 1, M Biel 1
PMCID: PMC1171315  PMID: 10228147

Abstract

Cardiac pacemaking is produced by the slow diastolic depolarization phase of the action potential. The hyperpolarization-activated cation current (If) forms an important part of the pacemaker depolarization and consists of two kinetic components (fast and slow). Recently, three full-length cDNAs encoding hyperpolarization-activated and cyclic nucleotide-gated cation channels (HCN1-3) have been cloned from mouse brain. To elucidate the molecular identity of cardiac pacemaker channels, we screened a human heart cDNA library using a highly conserved neuronal HCN channel segment and identified two cDNAs encoding HCN channels. The hHCN2 cDNA codes for a protein of 889 amino acids. The HCN2 gene is localized on human chromosome 19p13.3 and contains eight exons spanning approximately 27 kb. The second cDNA, designated hHCN4, codes for a protein of 1203 amino acids. Northern blot and PCR analyses showed that both hHCN2 and hHCN4 are expressed in heart ventricle and atrium. When expressed in HEK 293 cells, either cDNA gives rise to hyperpolarization-activated cation currents with the hallmark features of native If. hHCN2 and hHCN4 currents differ profoundly from each other in their activation kinetics, being fast and slow, respectively. We thus conclude that hHCN2 and hHCN4 may underlie the fast and slow component of cardiac If, respectively.

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Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Ashford M. L., Bond C. T., Blair T. A., Adelman J. P. Cloning and functional expression of a rat heart KATP channel. Nature. 1994 Aug 11;370(6489):456–459. doi: 10.1038/370456a0. [DOI] [PubMed] [Google Scholar]
  2. Ashworth L. K., Batzer M. A., Brandriff B., Branscomb E., de Jong P., Garcia E., Garnes J. A., Gordon L. A., Lamerdin J. E., Lennon G. An integrated metric physical map of human chromosome 19. Nat Genet. 1995 Dec;11(4):422–427. doi: 10.1038/ng1295-422. [DOI] [PubMed] [Google Scholar]
  3. Baker K., Warren K. S., Yellen G., Fishman M. C. Defective "pacemaker" current (Ih) in a zebrafish mutant with a slow heart rate. Proc Natl Acad Sci U S A. 1997 Apr 29;94(9):4554–4559. doi: 10.1073/pnas.94.9.4554. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Biel M., Ludwig A., Zong X., Hofmann F. Hyperpolarization-activated cation channels: a multi-gene family. Rev Physiol Biochem Pharmacol. 1999;136:165–181. doi: 10.1007/BFb0032324. [DOI] [PubMed] [Google Scholar]
  5. Biel M., Zong X., Ludwig A., Sautter A., Hofmann F. Molecular cloning and expression of the Modulatory subunit of the cyclic nucleotide-gated cation channel. J Biol Chem. 1996 Mar 15;271(11):6349–6355. doi: 10.1074/jbc.271.11.6349. [DOI] [PubMed] [Google Scholar]
  6. Biel M., Zong X., Ludwig A., Sautter A., Hofmann F. Structure and function of cyclic nucleotide-gated channels. Rev Physiol Biochem Pharmacol. 1999;135:151–171. doi: 10.1007/BFb0033672. [DOI] [PubMed] [Google Scholar]
  7. Brown H. F., DiFrancesco D., Noble S. J. How does adrenaline accelerate the heart? Nature. 1979 Jul 19;280(5719):235–236. doi: 10.1038/280235a0. [DOI] [PubMed] [Google Scholar]
  8. Brown H. F., Giles W., Noble S. J. Membrane currents underlying activity in frog sinus venosus. J Physiol. 1977 Oct;271(3):783–816. doi: 10.1113/jphysiol.1977.sp012026. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Clapham D. E. Not so funny anymore: pacing channels are cloned. Neuron. 1998 Jul;21(1):5–7. doi: 10.1016/s0896-6273(00)80508-5. [DOI] [PubMed] [Google Scholar]
  10. Denyer J. C., Brown H. F. Pacemaking in rabbit isolated sino-atrial node cells during Cs+ block of the hyperpolarization-activated current if. J Physiol. 1990 Oct;429:401–409. doi: 10.1113/jphysiol.1990.sp018264. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. DiFrancesco D. A new interpretation of the pace-maker current in calf Purkinje fibres. J Physiol. 1981 May;314:359–376. doi: 10.1113/jphysiol.1981.sp013713. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. DiFrancesco D. Block and activation of the pace-maker channel in calf purkinje fibres: effects of potassium, caesium and rubidium. J Physiol. 1982 Aug;329:485–507. doi: 10.1113/jphysiol.1982.sp014315. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. DiFrancesco D., Ferroni A., Mazzanti M., Tromba C. Properties of the hyperpolarizing-activated current (if) in cells isolated from the rabbit sino-atrial node. J Physiol. 1986 Aug;377:61–88. doi: 10.1113/jphysiol.1986.sp016177. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. DiFrancesco D., Mangoni M. Modulation of single hyperpolarization-activated channels (i(f)) by cAMP in the rabbit sino-atrial node. J Physiol. 1994 Feb 1;474(3):473–482. doi: 10.1113/jphysiol.1994.sp020038. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. DiFrancesco D. Pacemaker mechanisms in cardiac tissue. Annu Rev Physiol. 1993;55:455–472. doi: 10.1146/annurev.ph.55.030193.002323. [DOI] [PubMed] [Google Scholar]
  16. DiFrancesco D., Tortora P. Direct activation of cardiac pacemaker channels by intracellular cyclic AMP. Nature. 1991 May 9;351(6322):145–147. doi: 10.1038/351145a0. [DOI] [PubMed] [Google Scholar]
  17. Doyle D. A., Morais Cabral J., Pfuetzner R. A., Kuo A., Gulbis J. M., Cohen S. L., Chait B. T., MacKinnon R. The structure of the potassium channel: molecular basis of K+ conduction and selectivity. Science. 1998 Apr 3;280(5360):69–77. doi: 10.1126/science.280.5360.69. [DOI] [PubMed] [Google Scholar]
  18. Irisawa H., Brown H. F., Giles W. Cardiac pacemaking in the sinoatrial node. Physiol Rev. 1993 Jan;73(1):197–227. doi: 10.1152/physrev.1993.73.1.197. [DOI] [PubMed] [Google Scholar]
  19. Krapivinsky G., Gordon E. A., Wickman K., Velimirović B., Krapivinsky L., Clapham D. E. The G-protein-gated atrial K+ channel IKACh is a heteromultimer of two inwardly rectifying K(+)-channel proteins. Nature. 1995 Mar 9;374(6518):135–141. doi: 10.1038/374135a0. [DOI] [PubMed] [Google Scholar]
  20. Lehmann H., Klein U. E. Familial sinus node dysfunction with autosomal dominant inheritance. Br Heart J. 1978 Nov;40(11):1314–1316. doi: 10.1136/hrt.40.11.1314. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Liu Z. W., Zou A. R., Demir S. S., Clark J. W., Nathan R. D. Characterization of a hyperpolarization-activated inward current in cultured pacemaker cells from the sinoatrial node. J Mol Cell Cardiol. 1996 Dec;28(12):2523–2535. doi: 10.1006/jmcc.1996.0244. [DOI] [PubMed] [Google Scholar]
  22. Ludwig A., Zong X., Jeglitsch M., Hofmann F., Biel M. A family of hyperpolarization-activated mammalian cation channels. Nature. 1998 Jun 11;393(6685):587–591. doi: 10.1038/31255. [DOI] [PubMed] [Google Scholar]
  23. Lüthi A., McCormick D. A. H-current: properties of a neuronal and network pacemaker. Neuron. 1998 Jul;21(1):9–12. doi: 10.1016/s0896-6273(00)80509-7. [DOI] [PubMed] [Google Scholar]
  24. Mackintosh A. F., Chamberlain D. A. Sinus node disease affecting both parents and both children. Eur J Cardiol. 1979 Aug;10(2):117–122. [PubMed] [Google Scholar]
  25. Maruoka F., Nakashima Y., Takano M., Ono K., Noma A. Cation-dependent gating of the hyperpolarization-activated cation current in the rabbit sino-atrial node cells. J Physiol. 1994 Jun 15;477(Pt 3):423–435. doi: 10.1113/jphysiol.1994.sp020204. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Pape H. C. Queer current and pacemaker: the hyperpolarization-activated cation current in neurons. Annu Rev Physiol. 1996;58:299–327. doi: 10.1146/annurev.ph.58.030196.001503. [DOI] [PubMed] [Google Scholar]
  27. Porciatti F., Pelzmann B., Cerbai E., Schaffer P., Pino R., Bernhart E., Koidl B., Mugelli A. The pacemaker current I(f) in single human atrial myocytes and the effect of beta-adrenoceptor and A1-adenosine receptor stimulation. Br J Pharmacol. 1997 Nov;122(5):963–969. doi: 10.1038/sj.bjp.0701473. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Santoro B., Liu D. T., Yao H., Bartsch D., Kandel E. R., Siegelbaum S. A., Tibbs G. R. Identification of a gene encoding a hyperpolarization-activated pacemaker channel of brain. Cell. 1998 May 29;93(5):717–729. doi: 10.1016/s0092-8674(00)81434-8. [DOI] [PubMed] [Google Scholar]
  29. Sarachek N. S., Leonard J. L. Familial heart block and sinus bradycardia. Classification and natural history. Am J Cardiol. 1972 Apr;29(4):451–458. doi: 10.1016/0002-9149(72)90432-8. [DOI] [PubMed] [Google Scholar]
  30. Solomon J. S., Nerbonne J. M. Two kinetically distinct components of hyperpolarization-activated current in rat superior colliculus-projecting neurons. J Physiol. 1993 Sep;469:291–313. doi: 10.1113/jphysiol.1993.sp019815. [DOI] [PMC free article] [PubMed] [Google Scholar]
  31. Thuringer D., Lauribe P., Escande D. A hyperpolarization-activated inward current in human myocardial cells. J Mol Cell Cardiol. 1992 May;24(5):451–455. doi: 10.1016/0022-2828(92)91833-q. [DOI] [PubMed] [Google Scholar]
  32. Wickman K., Nemec J., Gendler S. J., Clapham D. E. Abnormal heart rate regulation in GIRK4 knockout mice. Neuron. 1998 Jan;20(1):103–114. doi: 10.1016/s0896-6273(00)80438-9. [DOI] [PubMed] [Google Scholar]
  33. Yanagihara K., Irisawa H. Inward current activated during hyperpolarization in the rabbit sinoatrial node cell. Pflugers Arch. 1980 May;385(1):11–19. doi: 10.1007/BF00583909. [DOI] [PubMed] [Google Scholar]
  34. Yu H., Chang F., Cohen I. S. Pacemaker current i(f) in adult canine cardiac ventricular myocytes. J Physiol. 1995 Jun 1;485(Pt 2):469–483. doi: 10.1113/jphysiol.1995.sp020743. [DOI] [PMC free article] [PubMed] [Google Scholar]
  35. Zagotta W. N., Siegelbaum S. A. Structure and function of cyclic nucleotide-gated channels. Annu Rev Neurosci. 1996;19:235–263. doi: 10.1146/annurev.ne.19.030196.001315. [DOI] [PubMed] [Google Scholar]

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