Comprehensive Physiology Wiley Online Library

Newly Cloned Threshold Channels

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., , 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., , 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.

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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