Comprehensive Physiology Wiley Online Library
For Librarians For Authors Editors About

Newly Cloned Threshold Channels

Dorothy A. Hanck, Ruth L. Martin, Jan Tytgat, Chris Ulens

10.1002/cphy.cp020118

Source: Supplement 6: Handbook of Physiology, The Cardiovascular System, The Heart

Originally published: 2002

Published online: January 2011

Full Article on Wiley Online Library



Abstract

The sections in this article are:

1 The Pacemaker Current (If, Ih, or HCN)
2 Molecular Cloning
3 Structure of HCN Channels
4 Distribution Patterns of HCN Genes
5 Biophysical Properties of HCN Channels
6 Low‐Voltage Activated Calcium Channels
7 Molecular Cloning and Distribution
8 Structure
9 Biophysics
9.1 Comparison of α1G, α1H, and α1I
9.2 How Voltage Dependent Are T‐type Calcium Channels?
9.3 Selectivity and Block of T‐Type Calcium Channels
10 Summary
Figure 1. Figure 1.

Representative mHCN1 and mHCN2 current traces are shown in upper and lower panels, respectively. The two‐microelectrode voltage‐clamp technique (GeneClamp 500, Axon Instruments, USA) was used to measure hyperpolarization‐activated currents evoked from Xenopus oocytes expressing either mHCN1 or mHCN2 cRNA (cDNA clones were a kind gift from Steven A. Siegelbaum, Columbia University, New York). Experiments were carried out using a high‐potassium (HK) external solution (composition in mM: KCl 96, NaCl 2, MgCl2 1, CaCl2 1.8, HEPES 5, and pH 7.5). Currents were filtered at 200 Hz, using a 4‐pole low‐pass Bessel filter. To eliminate the effect of the voltage drop across the bath‐grounding electrode, the bath potential was actively controlled. Capacitative and leak components were offline subtracted. For mHCN1, current traces were evoked by application of 1 sec hyper‐polarizing test pulses from −45 to −115 mV in 5 mV steps from a holding potential of −40mV (A). The pulse interval was 3 sec. Tail currents were measured at −40 mV (C). For mHCN2, current traces were evoked by application of 3 sec hyperpolarizing test pulses from −60 to −130 mV in 5 mV steps from a holding potential of −40 mV (B). The pulse interval was 4 sec. Only the first second of the pulses is shown for comparison with mHCN1 (A). Both traces are plotted on the same time scale; the scale bar in B also applies to A. mHCN2 tail currents were measured at −40mV (D) and plotted on the same time scale as mHCN1 tail currents (C). The time scale bar in D also applies to C.
Figure 2. Figure 2.

Selectivity filters for sodium channel high‐voltage activated Ca channel (hvA) and low‐voltage activated Ca channel (lvA).
Figure 3. Figure 3.

Alignment of S4 regions of voltage‐gated ion channels.
Figure 4. Figure 4.

Expression of T‐type Ca currents in HEK 293 cells with 2 mM Ca2+o as the charge carrier, a) Families of current traces from representative cells expressing α1G, α1H, and α1I. Currents were recorded from a holding potential of −100 mV, stepping from −80 to +20 mV in 5 mV increments once every 5 sec. Recordings were made at 22°C. b) Current‐voltage relationships from data in panel a showing peak current normalized to cell capacitance. Alpha 1G (•), Alpha 1H (▴), and Alpha 1I (▪), C time to peak current plotted as a function of voltage

From Martin et al., 86, with permission
Figure 5. Figure 5.

Current response from HEK293 cells stably expressing either a1G or a1I in response to an action potential clamp. The action potential was recorded from a canine cardiac Purkinje cell (kindly provided by S. Nattel).
Figure 6. Figure 6.

Slope factor (k) from fits to a Boltzmann relationship (G = Gmax / (1 + exp [(V‐V1/2/k)] as a function of the size of the currents (Gmax) for currents recorded in HEK293 cells expressing either α1G (▪) or α1H (•).
Figure 7. Figure 7.

Top panel shows representative sweeps with activity from single‐channel cell attached recordings of α1H in step depolarizations from −100 mV to −20 mV. Data are shown at 10 kHz, filtered at 1kHz. Dashed lines indicate the zero current and open‐channel amplitudes. Bottom panel shows sweeps with activity in the same cell when after 10 msec at 0 mV potential was changed to −100 mV. These were chosen because they showed multiple openings. To aid in comparison with data in the literature, 110 mM Ba was used as the charge carrier, and recordings were made at 22°C.


Figure 1.

Representative mHCN1 and mHCN2 current traces are shown in upper and lower panels, respectively. The two‐microelectrode voltage‐clamp technique (GeneClamp 500, Axon Instruments, USA) was used to measure hyperpolarization‐activated currents evoked from Xenopus oocytes expressing either mHCN1 or mHCN2 cRNA (cDNA clones were a kind gift from Steven A. Siegelbaum, Columbia University, New York). Experiments were carried out using a high‐potassium (HK) external solution (composition in mM: KCl 96, NaCl 2, MgCl2 1, CaCl2 1.8, HEPES 5, and pH 7.5). Currents were filtered at 200 Hz, using a 4‐pole low‐pass Bessel filter. To eliminate the effect of the voltage drop across the bath‐grounding electrode, the bath potential was actively controlled. Capacitative and leak components were offline subtracted. For mHCN1, current traces were evoked by application of 1 sec hyper‐polarizing test pulses from −45 to −115 mV in 5 mV steps from a holding potential of −40mV (A). The pulse interval was 3 sec. Tail currents were measured at −40 mV (C). For mHCN2, current traces were evoked by application of 3 sec hyperpolarizing test pulses from −60 to −130 mV in 5 mV steps from a holding potential of −40 mV (B). The pulse interval was 4 sec. Only the first second of the pulses is shown for comparison with mHCN1 (A). Both traces are plotted on the same time scale; the scale bar in B also applies to A. mHCN2 tail currents were measured at −40mV (D) and plotted on the same time scale as mHCN1 tail currents (C). The time scale bar in D also applies to C.



Figure 2.

Selectivity filters for sodium channel high‐voltage activated Ca channel (hvA) and low‐voltage activated Ca channel (lvA).



Figure 3.

Alignment of S4 regions of voltage‐gated ion channels.



Figure 4.

Expression of T‐type Ca currents in HEK 293 cells with 2 mM Ca2+o as the charge carrier, a) Families of current traces from representative cells expressing α1G, α1H, and α1I. Currents were recorded from a holding potential of −100 mV, stepping from −80 to +20 mV in 5 mV increments once every 5 sec. Recordings were made at 22°C. b) Current‐voltage relationships from data in panel a showing peak current normalized to cell capacitance. Alpha 1G (•), Alpha 1H (▴), and Alpha 1I (▪), C time to peak current plotted as a function of voltage

From Martin et al., 86, with permission


Figure 5.

Current response from HEK293 cells stably expressing either a1G or a1I in response to an action potential clamp. The action potential was recorded from a canine cardiac Purkinje cell (kindly provided by S. Nattel).



Figure 6.

Slope factor (k) from fits to a Boltzmann relationship (G = Gmax / (1 + exp [(V‐V1/2/k)] as a function of the size of the currents (Gmax) for currents recorded in HEK293 cells expressing either α1G (▪) or α1H (•).



Figure 7.

Top panel shows representative sweeps with activity from single‐channel cell attached recordings of α1H in step depolarizations from −100 mV to −20 mV. Data are shown at 10 kHz, filtered at 1kHz. Dashed lines indicate the zero current and open‐channel amplitudes. Bottom panel shows sweeps with activity in the same cell when after 10 msec at 0 mV potential was changed to −100 mV. These were chosen because they showed multiple openings. To aid in comparison with data in the literature, 110 mM Ba was used as the charge carrier, and recordings were made at 22°C.

References
 1. Accili, E. A., G. Redaelli, and D. DiFrancesco. Differential control of the hyperpolarization‐activated current (i(f)) by cAMP gating and phosphatase inhibition in rabbit sino‐atrial node myocytes. J. Physiol. (Lond.) 500: 643–51, 1997.
 2. Akaike, N., H. Kanaide, T. Kuga, M. Nakamura, J. Sadoshima, and H. Tomoike. Low‐voltage‐activated calcium current in rat aorta smooth muscle cells in primary culture. J. Physiol. (Lond.) 416: 141–160, 1989.
 3. Almers, W. and E. W. McCleskey. Non‐selective conductance in calcium channels of frog muscle: calcium selectivity in a singlefile pore. J. Physiol. (Lond.) 353: 585–608, 1984.
 4. Anderson, J. A., S. S. Huprikar, L. V. Kochian, W. J. Lucas, and R. F. Gaber. Functional expression of a probable Arabidopsis thaliana potassium channel in Saccharomyces cerevisiae. Proc. Natl. Acad. Sci. U.S.A. 89: 3736–3740, 1992.
 5. Anderson, O. and R. Koeppe. Molecular determinants of channel function. Physiol. Rev. 72: S89–S158., 1992.
 6. Arnoult, C., R. A. Cardullo, J. R. Lemos, and H. M. Florman. Activation of mouse sperm T‐type Ca2+ channels by adhesion to the egg zona pellucida. Proc. Natl. Acad. Sci. U.S.A. 93: 13004–13009, 1996.
 7. Balke, C. W. and W. G. Wier. Modulation of L‐type calcium channels by sodium ions. Proc. Natl. Acad. Sci. U.S.A. 89: 4417–4421, 1992.
 8. Bean, B. P. Two kinds of calcium channels in canine atrial cells. Differences in kinetics, selectivity, and pharmacology. J. Gen. Physiol. 86: 1–30, 1985.
 9. Beuckelmann, D. J., M. Nabauer, and E. Erdmann. Characteristics of calcium‐current in isolated human ventricular myocytes from patients with terminal heart failure. J. Mol. Cell. Cardiol. 23: 929–937, 1991.
 10. Biel, M., A. Ludwig, X. Zong, and F. Hofmann. Hyperpolarization‐activated cation channels: a multi‐gene family. Rev. Physiol. Biochem. Pharmacol. 136: 165–81, 1999.
 11. Bijlenga, P., J. H. Liu, E. Espinos, C. A. Haenggeli, J. Fischer‐Lougheed, C. R. Bader, and L. Bernheim. T‐type alpha 1H Ca2+ channels are involved in Ca2+ signaling during terminal differentiation (fusion) of human myoblasts. Proc. Natl. Acad. Sci. U.S.A. 97: 7627–7632, 2000.
 12. Bohn, G., S. Moosmang, H. Conrad, A. Ludwig, F. Hofmann, and N. Klugbauer. Expression of T‐ and L‐type calcium channel mRNA in mrine sinoatrial node. FEBS Lett. 481: 73–76, 2000.
 13. BoSmith, R. E., I. Briggs, and N. C. Sturgess. Inhibitory actions of ZENECA ZD7288 on whole‐cell hyperpolarization activated inward current (If) in guinea‐pig dissociated sinoatrial node cells. Br. J. Pharmacol. 110: 343–349, 1993.
 14. Bossu, J. L. and A. Feltz. Inactivation of the low‐threshold transient calcium current in rat sensory neurones: evidence for a dual process. J. Physiol. (Lond.) 376: 341–357, 1986.
 15. Bourinet, E., G. W. Zamponi, A. Stea, T. W. Soong, B. A. Lewis, L. P. Jones, D. T. Yue, and T. P. Snutch. The alpha 1E calcium channel exhibits permeation properties similar to low‐voltage‐activated calcium channels. J. Neurosci. 16: 4983–4993, 1996.
 16. Brogden, R. N. and A. Markham. Mibefradil. A review of its pharmacodynamic and pharmacokinetic properties, and therapeutic efficacy in the management of hypertension and angina pectoris [published erratum appears in Drugs 1998 Apr;55: 517]. Drugs 54: 774–793, 1997.
 17. Brotto, M. A. and T. L. Creazzo. Ca2+ transients in embryonic chick heart: contributions from Ca2+ channels and the sarcoplasmic reticulum. Am. J. Physiol. 270 (Heart Circ. Physiol.): H518–H525, 1996.
 18. Brown, H. and D. Difrancesco. Voltage‐clamp investigations of membrane currents underlying pace‐maker activity in rabbit sino‐atrial node. J. Physiol. (Lond.) 308: 331–351, 1980.
 19. Brown, H. F., D. DiFrancesco, and S. J. Noble. How does adrenaline accelerate the heart? Nature 280: 235–236, 1979.
 20. Brugge, J. S., P. C. Cotton, A. E. Queral, J. N. Barrett, D. Nonner, and R. W. Keane. Neurones express high levels of a structurally modified, activated form of pp60c‐src. Nature 316: 554–557, 1985.
 21. Budde, T., G. Biella, T. Munsch, and H. C. Pape. Lack of regulation by intracellular Ca2+ of the hyperpolarization‐activated cation current in rat thalamic neurones. J. Physiol. (Lond.) 503: 79–85, 1997.
 22. Carbone, E. and H. D. Lux. A low voltage‐activated calcium conductance in embryonic chick sensory neurons. Biophys. J. 46: 413–418, 1984.
 23. Chahine, M., A. L. George, Jr., M. Zhou, S. Ji, W. Sun, R. L. Barchi, and R. Horn. Sodium channel mutations in paramyotonia congenita uncouple inactivation from activation. Neuron 12: 281–294, 1994.
 24. Chemin, J., A. Monteil, E. Rourinet, J. Nargeot, and P. Lory. Alternatively spliced α1G (Cav3.1) intracellular loops promote specific T‐Type Ca2+ channel gating properties. Biophys. J. 80: 1238–1250, 2001.
 25. Chen, C. F. and P. Hess. Mechanism of gating of T‐type calcium channels. J. Gen. Physiol. 96: 603–630, 1990.
 26. Chen, J., J. Mitcheson, and M. Sanguinetti. Structural determinants of HCN channel gating: minimal functional unit and mutational analysis of the S4 domain. Biophys. J. 78: 1209, 2000.
 27. Clapham, D. E. Not so funny anymore: pacing channels are cloned. Neuron 21: 5–7, 1998.
 28. Cohen, C. J., R. T. McCarthy, P. Q. Barrett, and H. Rasmussen. Ca channels in adrenal glomerulosa cells: K+ and angiotensin II increase T‐type Ca channel current. Proc. Natl. Acad. Sci. U.S.A. 85: 2412–2416, 1988.
 29. Cohen, N. M. and W. J. Lederer. Calcium current in isolated neonatal rat ventricular myocytes. J. Physiol. (Lond.) 391: 169–191, 1987.
 30. Coulter, D. A., J. R. Huguenard, and D. A. Prince. Differential effects of petit mal anticonvulsants and convulsants on thalamic neurones: calcium current reduction. Br. J. Pharmacol. 100: 800–806, 1990.
 31. Cribbs, L. L., J. C. Gomora, A. N. Daud, J. H. Lee, and E. Perez‐Reyes. Molecular cloning and functional expression of Ca(v)3.1c, a T‐type calcium channel from human brain [published erratum appears in FEBS Lett 2000 Mar 31;470:378]. FEBS Lett 466: 54–58, 2000.
 32. Cribbs, L. L., J. H. Lee, J. Yang, J. Satin, Y. Zhang, A. Daud, J. Barclay, M. P. Williamson, M. Fox, M. Rees, and E. Perez‐Reyes. Cloning and characterization of alpha 1H from human heart, a member of the T‐type Ca2+ channel gene family. Circ. Res. 83: 103–109, 1998.
 33. Dang, T. X. and E. W. McCleskey. Ion channel selectivity through stepwise changes in binding affinity. J. Physiol. (Lond.) 111: 185–193, 1998.
 34. Delisle, B. P. and J. Satin. pH modification of human T‐type calcium channel gating. Biophys. J. 78: 1895–1905, 2000.
 35. DiFrancesco, D. Characterization of single pacemaker channels in cardiac sino‐atrial node cells. Nature 324: 470–473, 1986.
 36. DiFrancesco, D. Dual allosteric modulation of pacemaker (f) channels by cAMP and voltage in rabbit SA node. J. Physiol. (Lond.) 515: 367–376, 1999.
 37. DiFrancesco, D. A new interpretation of the pace‐maker current in calf Purkinje fibres. J. Physiol. (Lond.) 314: 359–376, 1981.
 38. DiFrancesco, D. The pacemaker current in the sinus node. Eur. Heart. J. 8 (Suppl L): 19–23, 1987.
 39. DiFrancesco, D. Pacemaker mechanisms in cardiac tissue. Annu. Rev. Physiol. 55: 455–472, 1993.
 40. DiFrancesco, D. and M. Mangoni. Modulation of single hyperpolarization‐activated channels (i(f)) by cAMP in the rabbit sino‐atrial node. J. Physiol. (Lond.) 474: 473–482, 1994.
 41. Doyle, D. A., J. Morais Cabral, R. A. Pfuetzner, A. Kuo, J. M. Gulbis, S. L. Cohen, B. T. Chait, and R. MacKinnon. The structure of the potassium channel: molecular basis of K+ conduction and selectivity [see comments]. Science 280: 69–77, 1998.
 42. Droogmans, G. and B. Nilius. Kinetic properties of the cardiac T‐type calcium channel in the guinea‐pig. J. Physiol. (Lond.) 419: 627–650, 1989.
 43. Ellinor, P. T., J. Yang, W. A. Sather, J. F. Zhang, and R. W. Tsien. Ca2+ channel selectivity at a single locus for high‐affinity Ca2+ interactions. Neuron 15: 1121–1132, 1995.
 44. Enyeart, J. J., B. Mlinar, and J. A. Enyeart. T‐type Ca2+ channels are required for adrenocorticotropin‐stimulated cortisol production by bovine adrenal zona fasciculata cells. Mol. Endocrinol. 7: 1031–1040, 1993.
 45. Ertel, E. A., K. P. Campbell, M. M. Harpold, F. Hofmann, Y. Mori, E. Perez‐Reyes, A. Schwartz, T. P. Snuth, T. Tanabe, L. Birnbaumer, R. W. Tsien, and W. A. Catterall. Nomenclature of voltage‐gated calcium channels. Neuron 25: 533–535, 2000.
 46. Ertel, S. I. and E. A. Ertel. Low‐voltage‐activated T‐type Ca2+ channels. Trends Pharmacol. Sci. 18: 37–42, 1997.
 47. Ertel, S. I., E. A. Ertel, and J. P. Clozel. T‐type Ca2+ channels and pharmacological blockade: potential pathophysiological relevance. Cardiovasc. Drugs. Ther. 11: 723–739, 1997.
 48. Fareh, S., A. Benardeau, B. Thibault, and S. Nattel. The T‐Type Ca2+ channel blocker mibefradil prevents the development of a substrate for atrial fibrillation by tachycardia‐induced atrial remodeling in dogs. Circ. Res. 100: 2191–2197, 1999.
 49. Fedulova, S. A., P. G. Kostyuk, and N. S. Veselovsky. Two types of calcium channels in the somatic membrane of new‐born rat dorsal root ganglion neurones. J. Physiol. (Lond.) 359: 431–446, 1985.
 50. Furukawa, T., H. Ito, J. Nitta, M. Tsujino, S. Adachi, M. Hiroe, F. Marumo, T. Sawanobori, and M. Hiraoka. Endothelin‐1 enhances calcium entry through T‐type calcium channels in cultured neonatal rat ventricular myocytes. Circ. Res. 71: 1242–1253, 1992.
 51. Gauss, R., R. Seifert, and U. B. Kaupp. Molecular identification of a hyperpolarization‐activated channel in sea urchin sperm. Nature 393: 583–587, 1998.
 52. Goulding, E. H., G. R. Tibbs, and S. A. Siegelbaum. Molecular mechanism of cyclic‐nucleotide‐gated channel activation. Nature 372: 369–374, 1994.
 53. Grisar, T., B. Lakaye, and E. Thomas. Molecular basis of neuronal biorhythms and paroxysms. Arch. Physiol. Biochem. 104: 770–774, 1996.
 54. Guy, H. R. and F. Conti. Pursuing the structure and function of voltage‐gated channels. Trends Neurosci. 13: 201–206, 1990.
 55. Hagiwara, N. and H. Irisawa. Modulation by intracellular Ca2+ of the hyperpolarization‐activated inward current in rabbit single sino‐atrial node cells. J. Physiol. (Lond.) 409: 121–141, 1989.
 56. Hagiwara, N., H. Irisawa, and M. Kameyama. Contribution of two types of calcium currents to the pacemaker potentials of rabbit sino‐atrial node cells. J. Physiol. (Lond.) 395: 233–253, 1988.
 57. Hagiwara, S., S. Ozawa, and O. Sand. Voltage clamp analysis of two inward current mechanisms in the egg cell membrane of a starfish. J. Gen. Physiol. 65: 617–644, 1975.
 58. Hancox, J. C. and A. J. Levi. L‐type calcium current in rod‐ and spindle‐shaped myocytes isolated from rabbit atrioventricular node. Am. J. Physiol. 267 (Heart Circ. Physiol.): H1670–H1680, 1994.
 59. Heginbotham, L., Z. Lu, T. Abramson, and R. MacKinnon. Mutations in the K+ channel signature sequence. Biophys. J. 66: 1061–1067, 1994.
 60. Hermsmeyer, K. Role of T channels in cardiovascular function. Cardiology 89: 2–9, 1998.
 61. Herrington, J. and C. J. Lingle. Kinetic and pharmacological properties of low voltage‐activated Ca2+ current in rat clonal (GH3) pituitary cells. J. Neurophysiol. 68: 213–232, 1992.
 62. Hess, P. and R. W. Tsien. Mechanism of ion permeation through calcium channels. Nature 309: 453–456, 1984.
 63. Hille, B. Ionic Channels of Excitable Membranes, Second Ed. Sinauer Associates Inc., 1992.
 64. Hille, B. Ionic selectivity of Na and K channels of nerve membranes. In: Membranes 3 edited by G. Eisenman. New York: Marcel Dekker, 1975: 255–325.
 65. Hirano, Y., H. A. Fozzard, and C. T. January. Characteristics of L‐ and T‐type Ca2+ currents in canine cardiac Purkinje cells. Am. J. Physiol. 256 (Heart Circ. Physiol.): H1478–H492, 1989.
 66. Huang, B., D. Qin, L. Deng, M. Boutjdir, and N. El‐Sherif. Reexpression of T‐type Ca2+ channel gene and current in postinfarction remodeled rat left ventricle. Cardiovasc. Res. 46: 442–449, 2000.
 67. Hughes, S. W., D. W. Cope, T. I. Toth, S. R. Williams, and V. Crunelli. All thalamocortical neurones possess a T‐type Ca2+ “window” current that enables the expression of bistability‐mediated activities. J. Physiol. (Lond.) 517: 805–815, 1999.
 68. Huguenard, J. R. Low‐threshold calcium currents in central nervous system neurons. Annu. Rev. Physiol. 58: 329–348, 1996.
 69. Ishii, T. M., M. Takano, L. H. Xie, A. Noma, and H. Ohmori. Molecular characterization of the hyperpolarization‐activated cation channel in rabbit heart sinoatrial node. J. Biol. Chem. 274: 12835–12839, 1999.
 70. Jahnsen, H. and R. Llinas. Voltage‐dependent burst‐to‐tonic switching of thalamic cell activity: an in vitro study. Arch. Ital. Biol. 122: 73–82, 1984.
 71. Janssen, L. J., D. K. Walters, and J. Wattie. Regulation of [Ca2+]i in canine airway smooth muscle by Ca(2+)‐ATPase and Na+/Ca2+ exchange mechanisms. Am. J. Physiol. 273 (Lung Physiol.): L322–L330, 1997.
 72. Kass, R. S. and M. C. Sanguinetti. Inactivation of calcium channel current in the calf cardiac Purkinje fiber. J. Gen. Physiol. 84: 705–726., 1984.
 73. Kawai, F. Odorants suppress T‐ and L‐type Ca2+ currents in olfactory receptor cells by shifting their inactivation curves to a negative voltage. Neurosci. Res. 35: 253–263, 1999.
 74. Kawano, S. and R. L. DeHaan. Analysis of the T‐type calcium channel in embryonic chick ventricular myocytes. J. Membr. Biol. 116: 9–17, 1990.
 75. Klockner, U., J. H. Lee, L. L. Cribbs, A. Daud, J. Hescheler, A. Pereverzev, E. Perez‐Reyes, and T. Schneider. Comparison of the Ca2+ currents induced by expression of three cloned alpha1 subunits, alpha1G, alpha1H and alpha1I, of low‐voltage‐activated T‐type Ca2+ channels. Eur. J. Neurosci. 11: 4171–4178, 1999.
 76. Kobrin, I., V. Charlon, E. Lindberg, and R. Pordy. Safety of mibefradil, a new once‐a‐day, selective T‐type calcium channel antagonist. Am. J. Cardiol. 80: 40C–46C, 1997.
 77. Kuga, T., S. Kobayashi, Y. Hirakawa, H. Kanaide, and A. Takeshita. Cell cycle‐dependent expression of L‐ and T‐type Ca2+ currents in rat aortic smooth muscle cells in primary culture. Circ. Res. 79: 14–19, 1996.
 78. Kunze, R. S., R. L. Martin, M. C. Emerick, W. S. Agnew, and D. A. Hanck. Kinetic differences in splice variance of the alpha1G T‐type calcium channel. Biophys. J. 78: 458A, 2000.
 79. Lacinova, L., N. Klugbauer, and F. Hofmann. Regulation of the calcium channel alpha(1G) subunit by divalent cations and organic blockers Neuropharmacology 39: 1254–1266, 2000.
 80. Lee, J. H., A. N. Daud, L. L. Cribbs, A. E. Lacerda, A. Pereverzev, U. Klockner, T. Schneider, and E. Perez‐Reyes. Cloning and expression of a novel member of the low voltage‐activated T‐type calcium channel family. J. Neurosci. 19: 1912–1921, 1999.
 81. Lee, J. H., J. C. Gomora, L. L. Cribbs, and E. Perez‐Reyes. Nickel block of three cloned T‐type calcium channels: low concentrations selectively block alpha1H. Biophys. J. 77: 3034–3042, 1999.
 82. Leuranguer, V., A. Monteil, E. Bourinet, G. Dayanithi, and J. Nargeot. T‐type calcium currents in rat cardiomyocytes during postnatal development: contribution to hormone secretion. Am. J. Physiol. Heart Circ. Physiol. 279: H2540–H2548, 2000.
 83. Li, J., J. Qu, and R. D. Nathan. Ionic basis of ryanodine's negative chronotropic effect on pacemaker cells isolated from the sinoatrial node. Am. J. Physiol. 273: H2481–H2489, 1997.
 84. Lipkind, G. M. and H. A. Fozzard. KcsA crystal structure as framework for a molecular model of the Na(+) channel pore [In Process Citation]. Biochemistry 39: 8161–8170, 2000.
 85. Lipkind, G. M., D. A. Hanck, and H. A. Fozzard. A structural motif for the voltage‐gated potassium channel pore. Proc. Natl. Acad. Sci. U.S.A. 92: 9215–9219, 1995.
 86. Ludwig, A., X. Zong, F. Hofmann, and M. Biel. Structure and function of cardiac pacemaker channels. Cell. Physiol. Biochem. 9: 179–186, 1999.
 87. Ludwig, A., X. Zong, M. Jeglitsch, F. Hofmann, and M. Biel. A family of hyperpolarization‐activated mammalian cation channels. Nature 393: 587–591, 1998.
 88. Ludwig, A., X. Zong, J. Stieber, R. Hullin, F. Hofmann, and M. Biel. Two pacemaker channels from human heart with profoundly different activation kinetics. Embo. J. 18: 2323–2329, 1999.
 89. Maccaferri, G., M. Mangoni, A. Lazzari, and D. DiFrancesco. Properties of the hyperpolarization‐activated current in rat hippocampal CA1 pyramidal cells. J. Neurophysiol. 69: 2129–2136, 1993.
 90. Marten, I. and T. Hoshi. The N‐terminus of the K channel KAT1 controls its voltage‐dependent gating by altering the membrane electric field. Biophys. J. 74: 2953–2962, 1998.
 91. Martin, R. L., J. H. Lee, L. L. Cribbs, E. Perez‐Reyes, and D. A. Hanck. Mibefradil block of cloned T‐type Ca channels. J. Pharm. Exp. Ther., 295: 302–308, 2000.
 92. Martinez, M. L., M. P. Heredia, and C. Delgado. Expression of T‐type Ca2+ channels in ventricular cells from hypertrophied rat hearts. J. Mol. Cell. Cardiol. 31: 1617–1625, 1999.
 93. Martinez, R., B. Mathey‐Prevot, A. Bernards, and D. Baltimore. Neuronal pp60c‐src contains a six‐amino acid insertion relative to its non‐neuronal counterpart. Science 237: 411–415, 1987.
 94. Matteson, D. R. and C. M. Armstrong. Properties of two types of calcium channels in clonal pituitary cells. J. Gen. Physiol. 87: 161–182, 1986.
 95. McCormick, D. A. and H. C. Pape. Properties of a hyperpolarization‐activated cation current and its role in rhythmic oscillation in thalamic relay neurones. J. Physiol. (Lond.) 431: 291–318, 1990.
 96. Miller, A. G. and R. W. Aldrich. Conversion of a delayed rectifier K+ channel to a voltage‐gated inward rectifier K+ channel by three amino acid substitutions. Neuron 16: 853–858, 1996.
 97. Mittman, S., J. Guo, and W. S. Agnew. Structure and alternative splicing of the gene encoding alpha1G, a human brain T calcium channel alpha1 subunit. Neurosci. Lett. 274: 143–146, 1999.
 98. Mittman, S., J. Guo, M. C. Emerick, and W. S. Agnew. Structure and alternative splicing of the gene encoding alpha1I, a human brain T calcium channel alpha1 subunit. Neurosci. Lett. 269: 121–124, 1999.
 99. Monteil, A., J. Chemin, E. Bourinet, G. Mennessier, P. Lory, and J. Nargeot. Molecular and functional properties of the human alpha(1G) subunit that forms T‐type calcium channels. J. Biol. Chem. 275: 6090–6100, 2000.
 100. Moosmang, S., M. Biel, F. Hofmann, and A. Ludwig. Differential distribution of four hyperpolarization‐activated cation channels in mouse brain. Biol. Chem. 380: 975–980, 1999.
 101. Narahashi, T., A. Tsunoo, and M. Yoshii. Characterization of two types of calcium channels in mouse neuroblastoma cells. J. Physiol. (Lond.) 383: 231–249, 1987.
 102. Nilius, B. Possible functional significance of a novel type of cardiac Ca channel. Biomed. Biochim. Acta 45: K37–K45, 1986.
 103. Nilius, B., P. Hess, J. B. Lansman, and R. W. Tsien. A novel type of cardiac calcium channel in ventricular cells. Nature 316: 443–446, 1985.
 104. Nowycky, M. C., A. P. Fox, and R. W. Tsien. Three types of neuronal calcium channel with different calcium agonist sensitivity. Nature 316: 440–443, 1985.
 105. Nuss, H. B. and S. R. Houser. T‐type Ca2+ current is expressed in hypertrophied adult feline left ventricular myocytes. Circ. Res. 73: 777–782, 1993.
 106. Nuss, H. B. and E. Marban. Electrophysiological properties of neonatal mouse cardiac myocytes in primary culture. J. Physiol. (Lond.) 479: 265–279, 1994.
 107. Ouadid, H., J. Seguin, S. Richard, P. A. Chaptal, and J. Nargeot. Properties and modulation of Ca channels in adult human atrial cells. J. Mol. Cell. Cardiol. 23: 41–54, 1991.
 108. Papazian, D. M., T. L. Schwarz, B. L. Tempel, Y. N. Jan, and L. Y. Jan. Cloning of genomic and complementary DNA from Shaker, a putative potassium channel gene from Drosophila. Science 237: 749–753, 1987.
 109. Pape, H. C. Queer current and pacemaker: the hyperpolarization‐activated cation current in neurons. Annu. Rev. Physiol. 58: 299–327, 1996.
 110. Pemberton, K. E., L. J. Hill‐Eubanks, S. V. Penelope Jones. Modulation of low‐threshold T‐type calcium channels by the five muscarinic receptor subtypes in NIH 3T3 cells. Pflugers Arch. 440: 452–461, 2000.
 111. Perchenet, L., A. Benardeau, and E. A. Ertel. Pharmacological properties of Ca(V)3.2, a low voltage‐activated Ca2+ channel cloned from human heart Naunyn‐Schmiedebergs Arch. Pharmacol. 361: 590–599, 2000.
 112. Perez‐Reyes, E. Molecular characterization of a novel family of low voltage‐activated, T‐type, calcium channels. J. Bioenerg. Biomembr. 30: 313–318, 1998.
 113. Perez‐Reyes, E., L. L. Cribbs, A. Daud, A. E. Lacerda, J. Barclay, M. P. Williamson, M. Fox, M. Rees, and J. H. Lee. Molecular characterization of a neuronal low‐voltage‐activated T‐type calcium channel [see comments]. Nature 391: 896–900, 1998.
 114. Piedras‐Renteria, E. S., C. C. Chen, and P. M. Best. Antisense oligonucleotides against rat brain alpha1E DNA and its atrial homologue decrease T‐type calcium current in atrial myocytes. Proc. Natl. Acad. Sci. U. S. A. 94: 14936–14941, 1997.
 115. Randall, A. D. and R. W. Tsien. Contrasting biophysical and pharmacological properties of T‐type and R‐type calcium channels. Neuropharmacology 36: 879–893, 1997.
 116. Ross C. A., J. D. Wood, G. Schilling, M. F. Peters, F. C. Nucifora, Jr., J. K. Cooper, A. H. Sharp, R. L. Margolis, and D. R. Borchelt. Polyglutamine pathogenesis. Philos. Trans. R. Soc. Lond. B. Biol. Sci. 354: 1005–1011, 1999.
 117. Sandmann, S., J. Y. Min, A. Meissner, and T. Unger. Effects of the calcium channel antagonist mibefradil on haemodynamic parameters and myocardial Ca(2+)‐handling in infarct‐induced heart failure in rats. Cardiovasc. Res. 44: 67–80, 1999.
 118. Santi, C.M., A. Darszon, and A. Hernandez‐Cruz. A dihydropyridine‐sensitive T‐type Ca2+ current is the main Ca2+ current carrier in mouse primary spermatocytes. Am. J. Physiol. 271 (Cell Physiol.): C1583–C1593, 1996.
 119. Santoro B., S. Chen, A. Luthi, P. Pavlidis, G. P. Shumyatsky, G. R. Tibbs, S. A. Siegelbaum. Molecular and functional heterogeneity of hyperpolarization‐activated pacemaker channels in the mouse CNS. J. Neurosci. 20: 5264–5275, 2000.
 120. Santoro, B., S. G. Grant, D. Bartsch, and E. R. Kandel. Interactive cloning with the SH3 domain of N‐src identifies a new brain specific ion channel protein, with homology to eag and cyclic nucleotide‐gated channels. Proc. Natl. Acad. Sci. U. S. A. 94: 14815–14820, 1997.
 121. Santoro, B., D. T. Liu, H. Yao, D. Bartsch, E. R. Kandel, S. A. Siegelbaum, and G. R. Tibbs. Identification of a gene encoding a hyperpolarization‐activated pacemaker channel of brain. Cell 93: 717–729, 1998.
 122. Santoro, B. and G. R. Tibbs. The HCN gene family: molecular basis of the hyperpolarization‐activated pacemaker channels. Ann. N. Y. Acad. Sci. 868: 741–764, 1999.
 123. Satoh, H. Role of T‐type Ca2+ channel inhibitors in the pacemaker depolarization in rabbit sino‐atrial nodal cells. Gen. Pharmacol. 26: 581–587, 1995.
 124. Seifert, R., A. Scholten, R. Gauss, A. Mincheva, P. Lichter, and U. B. Kaupp. Molecular characterization of a slowly gating human hyperpolarization‐activated channel predominantly expressed in thalamus, heart, and testis. Proc. Natl. Acad. Sci. U. S. A. 96: 9391–9396, 1999.
 125. Self, D. A., K. Bian, S. K. Mishra, and K. Hermsmeyer. Strokeprone SHR vascular muscle Ca2+ current amplitudes correlate with lethal increases in blood pressure. J. Vasc. Res. 31: 359–366, 1994.
 126. Sen, L. and T. W. Smith. T‐type Ca2+ channels are abnormal in genetically determined cardiomyopathic hamster hearts. Circ. Res. 75: 149–155, 1994.
 127. Sentenac, H., N. Bonneaud, M. Minet, F. Lacroute, J. M. Salmon, F. Gaymard, and C. Grignon. Cloning and expression in yeast of a plant potassium ion transport system. Science 256: 663–665, 1992.
 128. Seoh, S. A., D. Sigg, D. M. Papazian, and F. Bezanilla. Voltage‐sensing residues in the S2 and S4 segments of the Shaker K+ channel. Neuron 16: 1159–1167, 1996.
 129. Serrano, J. R., E. Perez‐Reyes, and S. W. Jones. State‐dependent inactivation of the alpha1G T‐type calcium channel. J. Gen. Physiol. 114: 185–201, 1999.
 130. Sesti, F., E. Eismann, U. B. Kaupp, M. Nizzari, and V. Torre. The multi‐ion nature of the cGMP‐gated channel from vertebrate rods. J. Physiol. (Lond.) 487: 17–36, 1995.
 131. Shabb, J. B., and J. D. Corbin. Cyclic nucleotide‐binding domains in proteins having diverse functions. J. Biol. Chem. 267: 5723–5726, 1992.
 132. Shi, W., R. Wymore, H. Yu, J. Wu, R. T. Wymore, Z. Pan, R. B. Robinson, J. E. Dixon, D. McKinnon, and I. S. Cohen. Distribution and prevalence of hyperpolarization‐activated cation channel (HCN) mRNA expression in cardiac tissues. Circ. Res. 85: e1–6, 1999.
 133. Shuba, Y. M., V. I. Teslenko, A. N. Savchenko, and N. H. Pogorelaya. The effect of permeant ions on single calcium channel activation in mouse neuroblastoma cells: ion‐channel interaction. J. Physiol. (Lond.) 443: 25–44, 1991.
 134. Sipido, K., E. Carmeliet, and F. VanDe Werf. T‐type Ca2+ current as a trigger for Ca2+ release from the sarcoplasmic reticulum in guinea‐pig ventricular myocytes. J. Physiol. (Lond.) 508: 439–452, 1998.
 135. Soltesz, I., S. Lightowler, N. Leresche, D. Jassik‐Gerschenfeld, C. E. Pollard, and V. Crunelli. Two inward currents and the transformation of low‐frequency oscillations of rat and cat thalamocortical cells. J. Physiol. (Lond.) 441: 175–197, 1991.
 136. Soong, T. W., A. Stea, C. D. Hodson, S. J. Dubel, S. R. Vincent, and T. P. Snutch. Structure and functional expression of a member of the low voltage‐activated calcium channel family. Science 260: 1133–1136, 1993.
 137. Staes, M., K. Talavera, N. Klugbauer, J. Prenen, L. Lacinova, G. Froogmans, F. Hofmann, and B. Nilius. The amino side of the C‐terminus determines fast inactivation of the T‐type calcium channel α1G J. Physiol. 530: 35–45, 2001.
 138. Suzuki, S. and M. A. Rogawski. T‐type calcium channels mediate the transition between tonic and phasic firing in thalamic neurons. Proc. Natl. Acad. Sci. U. S. A. 86: 7228–7232, 1989.
 139. Takahashi, K. and N. Akaike. Calcium antagonist effects on low‐threshold (T‐type) calcium current in rat isolated hippocampal CA1 pyramidal neurons. J. Pharmacol. Exp. Ther. 256: 169–175, 1991.
 140. Talley, E. M., L. L. Cribbs, J. H. Lee, A. Daud, E. Perez‐Reyes, and D. A. Bayliss. Differential distribution of three members of a gene family encoding low voltage‐activated (T‐type) calcium channels. J. Neurosci. 19: 1895–1911, 1999.
 141. Tsakiridou, E., L. Bertollini, M. de Curtis, G. Avanzini, and H. C. Pape. Selective increase in T‐type calcium conductance of reticular thalamic neurons in a rat model of absence epilepsy. J. Neurosci. 15: 3110–3117, 1995.
 142. Tseng, G. N. and P. A. Boyden. Multiple types of Ca2+ currents in single canine Purkinje cells. Circ. Res. 65: 1735–1750, 1989.
 143. Tsien, R. W. Key clockwork component cloned. Nature 391: 839–841, 1998.
 144. Tsien, R. W., J.‐P. Clozel, and J. Nargeot. Low‐voltage‐activated T‐Type calcium channels. Proceedings from the International Electrophysiology Meeting. Montpellier 21–22 October, 1996.
 145. Tytgat, J., B. Nilius, J. Vereecke, and E. Carmeliet. The T‐type Ca channel in guinea‐pig ventricular myocytes is insensitive to isoproterenol. Pflugers Arch. 411: 704–706, 1988.
 146. Ulens C. and J. Tytgat. Functional heteromerization of HCN1 and HCN2 pacemaker channels. J. Biol. Chem. 276: 6069–6072, 2001.
 147. Vaccari, T., A. Moroni, M. Rocchi, L. Gorza, M. E. Bianchi, M. Beltrame, and D. DiFrancesco. The human gene coding for HCN2, a pacemaker channel of the heart. Biochim. Biophys. Acta. 1446: 419–425, 1999.
 148. Van Bogaert, P. P. and M. Goethals. Pharmacological influence of specific bradycardic agents on the pacemaker current of sheep cardiac Purkinje fibres. A comparison between three different molecules. Eur. Heart J. 8 (Suppl L): 35–42, 1987.
 149. Williamson, A. V. and W. A. Sather. Nonglutamate pore residues in ion selection and conduction in voltage gated Ca2+ channels. Biophys. J. 77: 2575–2589, 1999.
 150. Wollmuth, L. P. Multiple ion binding sites in Ih channels of rod photoreceptors from tiger salamanders. Pflugers. Arch. 430: 34–43, 1995.
 151. Xiong, Z., N. Sperelakis, A. Noffsinger, and C. Fenoglio‐Preiser. Ca2+ currents in human colonic smooth muscle cells. Am. J. Physiol. 269 Gastrointest: G378–G85, 1995.
 152. Yanagihara, K. and H. Irisawa. Inward current activated during hyperpolarization in the rabbit sinoatrial node cell. Pflugers. Arch. 385: 11–19, 1980.
 153. Yeoman, M. S., B. L. Brezden, and P. R. Benjamin. LVA and HVA Ca(2+) currents in ventricular muscle cells of the Lymnaea heart. J. Neurophysiol. 82: 2428–2440, 1999.
 154. Yu, H., F. Chang, and I. S. Cohen. Pacemaker current exists in ventricular myocytes. Circ. Res. 72: 232–236, 1993.
 155. Zagotta, W. N. and S. A. Siegelbaum. Structure and function of cyclic nucleotide‐gated channels. Annu. Rev. Neurosci. 19: 235–263, 1996.
 156. Zhang, Y., L. L. Cribbs, and J. Satin. Arachidonic acid modulation of alpha1H, a cloned human T‐type calcium channel. Am. J. Physiol. 278: H184–H193, 2000.
 157. Zhou, Z. and C. T. January. Both T‐ and L‐type Ca2+ channels can contribute to excitation‐contraction coupling in cardiac Purkinje cells. Biophys. J. 74: 1830–1839, 1998.
 158. Zhou, Z. and S. L. Lipsius. Properties of the pacemaker current (If) in latent pacemaker cells isolated from cat right atrium. J. Physiol. (Lond.) 453: 503–523, 1992.
 159. Zhou, Z. and S. L. Lipsius. T‐type calcium current in latent pacemaker cells isolated from cat right atrium. J. Mol. Cell. Cardiol. 26: 1211–1219, 1994.

Contact Editor

Submit a note to the editor about this article by filling in the form below.

* Required Field

Article Title: Newly Cloned Threshold Channels
 

How to Cite

Dorothy A. Hanck, Ruth L. Martin, Jan Tytgat, Chris Ulens. Newly Cloned Threshold Channels. Compr Physiol 2011, Supplement 6: Handbook of Physiology, The Cardiovascular System, The Heart: 693-708. First published in print 2002. doi: 10.1002/cphy.cp020118