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Ion Channels in the Heart: Cellular and Molecular Properties of Cardiac Na, Ca, and K Channels

Bronagh Heath, Kevin Gingrich, Robert S. Kass

10.1002/cphy.cp020114

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 Calcium Channels
2 Sodium Channels
2.1 Primary Structure of the Voltage‐Gated Na+ Channel
2.2 Molecular Pharmacology of Na+ Channels
2.3 Molecular Pharmacology of an Inherited Disease
3 Potassium Channels
3.1 Voltage‐Dependent K+ Channels
3.2 Inward Rectifier K Channels
4 Summary
Figure 1. Figure 1.

Predicted topology for the α1 subunit of voltage‐gated potassium (A), and sodium or calcium (B) channels.

From Keating and Sanguinetti 128, with permission
Figure 2. Figure 2.

Schematic representation of the subunit composition of L‐type skeletal (left) and cardiac (right) calcium channels. Note that predicted PKA phosphorylation sites are indicated as solid squares.

From Hosey et al., 63 with permission
Figure 3. Figure 3.

The response of L‐type calcium channels to β‐AR stimulation changes with development. Response of currents measured in single murine embryonic cells to isoproterenol in early stage (a) and late stage (b) embryonic heart. The currents in the late, but not early, stage cells are enhanced by isoproterenol and this effect is due to an increase in intracellular cAMP.

From An et al., 3 with permission
Figure 4. Figure 4.

Recombinant channels formed by α1 subunits reconstitute voltage‐ and calcium‐dependent properties of native channels. Recordings from mammalian cells transfected with cDNA encoding the α1 subunit of smooth muscle L‐type calcium channels (α1c–b) (right‐hand panel) compared with L‐type channel activity measured in guinea pig ventricular myocytes (left‐hand panel). The rows compare current when barium (lower) or calcium (upper) is the charge carrier.

From Welling et al., 167, with permission
Figure 5. Figure 5.

Domain interface model of high‐affinity phenylalkylamine block of L‐type calcium channels. Location of pore region glutamates (A) and key amino acid residues in domains IIIS6 and IVS6 (white symbols on black circles) that, when mutated, disrupt block of channel activity by the charged phenylalkylamine (−)‐D888. Proposed model to explain block of channels postulates that convergence of the pore region of domains III and IV with key residues of IIIS6 forms the binding site for this drug.

From Hockerman et al. 183, with permission
Figure 6. Figure 6.

An inherited deletion mutation (KPQ) of the human sodium channel α subunit (hH1) promotes maintained current in response to prolonged depolarization. Currents measured from cells transfected with wild‐type (hH1) or mutant (KPQ) Na channel α subunits are shown for peak (left) and maintained (right) current. The KPQ mutation, which causes one form of the long QT syndrome, promotes additional maintained current (right), but does not affect peak currents.

From An et al. 3, with permission
Figure 7. Figure 7.

Simplified gating states for model Na channel. Transitions are allowed between rested (R), open (O), fast inactivated (IF) and slow inactivated (IS) states. Not indicated here are intermediate inactivated states of the channel as well as multiple open states. However, upper arrows indicate direct transitions between rested and inactivated states of the channel.
Figure 8. Figure 8.

Schematic of sequence of voltage‐gated Na channel alpha subunit. Note four homologous domains, each of which contains six helical transmembrane fragments. C‐ and N‐termini are intracellular.
Figure 9. Figure 9.

The local anesthetic drug lidocaine blocks maintained current through mutant LQT‐3 (KPQ) Na channels more potently than peak currents of either hH1 (wild‐type) or KPQ channels. Plotted is the fraction of current blocked for each channel construct in response to 100 μM lidocaine. These results strongly suggested that this type of drug might be useful in specifically treating the inherited arrhythmia LQT‐3 caused by this gene mutation.

From An et al. 3, with permission
Figure 10. Figure 10.

Multiple potassium channels in the developing mouse heart. Patch‐clamp recordings of murine embryonic ventricular cells reveals rapidly activating K channel current that inactivates rapidly (A), slowly (B), or not at all (C). These components in the mouse heart reflect Ito (left and center) and Iur (right).

From Davies et al. 182, with permission
Figure 11. Figure 11.

Two components of delayed rectifier potassium current are revealed by differential sensitivity to block by class III antiarrhythmic agents, Action potentials and membrane currents recorded in the absence (Curve C) and presence (Curve E) of 5 μM E‐4031. Difference currents (DIF) reveal the properties of the current blocked by the drug, which is called IKr. Lower panel shows the voltage‐dependence of activation of total delayed rectifier current (IK) as well as the two components: IKr (open circles) and IKs (open squares).

From Sanguinetti and Jurkiewicz 132, with permission
Figure 12. Figure 12.

Single‐channel recordings from inward rectifier channels indicate that rectification (the tendency to pass more current in one direction than another) occurs at the single‐channel level.

From Sakmann and Trube 185, with permission
Figure 13. Figure 13.

Reconstitution of IKATP. Co‐expression of inward rectifier subunit (Kir6.2) with, a the sulfonylurea receptor (SUR2A) encodes channel activity that demonstrates conductance, permeation, and ATP‐sensitivity of native IKATP channels

from Inagaki et al 65, with permission


Figure 1.

Predicted topology for the α1 subunit of voltage‐gated potassium (A), and sodium or calcium (B) channels.

From Keating and Sanguinetti 128, with permission


Figure 2.

Schematic representation of the subunit composition of L‐type skeletal (left) and cardiac (right) calcium channels. Note that predicted PKA phosphorylation sites are indicated as solid squares.

From Hosey et al., 63 with permission


Figure 3.

The response of L‐type calcium channels to β‐AR stimulation changes with development. Response of currents measured in single murine embryonic cells to isoproterenol in early stage (a) and late stage (b) embryonic heart. The currents in the late, but not early, stage cells are enhanced by isoproterenol and this effect is due to an increase in intracellular cAMP.

From An et al., 3 with permission


Figure 4.

Recombinant channels formed by α1 subunits reconstitute voltage‐ and calcium‐dependent properties of native channels. Recordings from mammalian cells transfected with cDNA encoding the α1 subunit of smooth muscle L‐type calcium channels (α1c–b) (right‐hand panel) compared with L‐type channel activity measured in guinea pig ventricular myocytes (left‐hand panel). The rows compare current when barium (lower) or calcium (upper) is the charge carrier.

From Welling et al., 167, with permission


Figure 5.

Domain interface model of high‐affinity phenylalkylamine block of L‐type calcium channels. Location of pore region glutamates (A) and key amino acid residues in domains IIIS6 and IVS6 (white symbols on black circles) that, when mutated, disrupt block of channel activity by the charged phenylalkylamine (−)‐D888. Proposed model to explain block of channels postulates that convergence of the pore region of domains III and IV with key residues of IIIS6 forms the binding site for this drug.

From Hockerman et al. 183, with permission


Figure 6.

An inherited deletion mutation (KPQ) of the human sodium channel α subunit (hH1) promotes maintained current in response to prolonged depolarization. Currents measured from cells transfected with wild‐type (hH1) or mutant (KPQ) Na channel α subunits are shown for peak (left) and maintained (right) current. The KPQ mutation, which causes one form of the long QT syndrome, promotes additional maintained current (right), but does not affect peak currents.

From An et al. 3, with permission


Figure 7.

Simplified gating states for model Na channel. Transitions are allowed between rested (R), open (O), fast inactivated (IF) and slow inactivated (IS) states. Not indicated here are intermediate inactivated states of the channel as well as multiple open states. However, upper arrows indicate direct transitions between rested and inactivated states of the channel.



Figure 8.

Schematic of sequence of voltage‐gated Na channel alpha subunit. Note four homologous domains, each of which contains six helical transmembrane fragments. C‐ and N‐termini are intracellular.



Figure 9.

The local anesthetic drug lidocaine blocks maintained current through mutant LQT‐3 (KPQ) Na channels more potently than peak currents of either hH1 (wild‐type) or KPQ channels. Plotted is the fraction of current blocked for each channel construct in response to 100 μM lidocaine. These results strongly suggested that this type of drug might be useful in specifically treating the inherited arrhythmia LQT‐3 caused by this gene mutation.

From An et al. 3, with permission


Figure 10.

Multiple potassium channels in the developing mouse heart. Patch‐clamp recordings of murine embryonic ventricular cells reveals rapidly activating K channel current that inactivates rapidly (A), slowly (B), or not at all (C). These components in the mouse heart reflect Ito (left and center) and Iur (right).

From Davies et al. 182, with permission


Figure 11.

Two components of delayed rectifier potassium current are revealed by differential sensitivity to block by class III antiarrhythmic agents, Action potentials and membrane currents recorded in the absence (Curve C) and presence (Curve E) of 5 μM E‐4031. Difference currents (DIF) reveal the properties of the current blocked by the drug, which is called IKr. Lower panel shows the voltage‐dependence of activation of total delayed rectifier current (IK) as well as the two components: IKr (open circles) and IKs (open squares).

From Sanguinetti and Jurkiewicz 132, with permission


Figure 12.

Single‐channel recordings from inward rectifier channels indicate that rectification (the tendency to pass more current in one direction than another) occurs at the single‐channel level.

From Sakmann and Trube 185, with permission


Figure 13.

Reconstitution of IKATP. Co‐expression of inward rectifier subunit (Kir6.2) with, a the sulfonylurea receptor (SUR2A) encodes channel activity that demonstrates conductance, permeation, and ATP‐sensitivity of native IKATP channels

from Inagaki et al 65, with permission
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Article Title: Ion Channels in the Heart: Cellular and Molecular Properties of Cardiac Na, Ca, and K Channels
 

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Bronagh Heath, Kevin Gingrich, Robert S. Kass. Ion Channels in the Heart: Cellular and Molecular Properties of Cardiac Na, Ca, and K Channels. Compr Physiol 2011, Supplement 6: Handbook of Physiology, The Cardiovascular System, The Heart: 548-567. First published in print 2002. doi: 10.1002/cphy.cp020114