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HCN channels--modulators of cardiac and neuronal excitability.

Herrmann S, Schnorr S, Ludwig A - Int J Mol Sci (2015)

Bottom Line: The data, which are mainly derived from studies using transgenic mice, suggest that HCN channels contribute significantly to cellular excitability in these tissues.Remarkably, the impact of the channels is clearly more pronounced in pathophysiological states including ventricular hypertrophy as well as neural inflammation and neuropathy suggesting that HCN channels may constitute promising drug targets in the treatment of these conditions.This perspective as well as the current therapeutic use of HCN blockers will also be addressed.

View Article: PubMed Central - PubMed

Affiliation: Institut für Experimentelle und Klinische Pharmakologie und Toxikologie, Friedrich-Alexander-Universität Erlangen-Nürnberg, 91054 Erlangen, Germany. Stefan.Herrmann@pharmakologie.uni-erlangen.de.

ABSTRACT
Hyperpolarization-activated cyclic nucleotide-gated (HCN) channels comprise a family of cation channels activated by hyperpolarized membrane potentials and stimulated by intracellular cyclic nucleotides. The four members of this family, HCN1-4, show distinct biophysical properties which are most evident in the kinetics of activation and deactivation, the sensitivity towards cyclic nucleotides and the modulation by tyrosine phosphorylation. The four isoforms are differentially expressed in various excitable tissues. This review will mainly focus on recent insights into the functional role of the channels apart from their classic role as pacemakers. The importance of HCN channels in the cardiac ventricle and ventricular hypertrophy will be discussed. In addition, their functional significance in the peripheral nervous system and nociception will be examined. The data, which are mainly derived from studies using transgenic mice, suggest that HCN channels contribute significantly to cellular excitability in these tissues. Remarkably, the impact of the channels is clearly more pronounced in pathophysiological states including ventricular hypertrophy as well as neural inflammation and neuropathy suggesting that HCN channels may constitute promising drug targets in the treatment of these conditions. This perspective as well as the current therapeutic use of HCN blockers will also be addressed.

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Mice lacking hyperpolarization-activated cyclic nucleotide-gated (HCN) 2+4 channels do not develop a significant prolongation of the action potential during ventricular hypertrophy. (A) Action potentials of ventricular myocytes isolated from control (CTR), hypertrophic control (TACCTR) and hypertrophic HCN2+4 knockout (TACKO) mice. Ventricular hypertrophy was induced by the transverse aortic constriction procedure (TAC); (B) Mean action potential durations (APD) of ventricular myocytes from controls (CTR, white), HCN2+4 knockouts (KO, black), hypertrophic controls (TACCTR, light grey) and hypertrophic HCN2+4 knockouts (TACKO, dark grey). n.s. means p > 0.05, **p < 0.01. (A) and (B) are taken from Hofmann, F. et al. [46]; (C) During ventricular hypertrophy, an increased activity of HCN channels, together with a decrease in potassium currents, counteracts the repolarization of the action potential. The resulting action potential prolongation increases the risk of early after depolarizations (EAD) which are an important cause of lethal ventricular arrhythmias. The diagram is partly based on [61]. If and IK are indicated by red and green stripes, respectivley. The development of ventricular hypertrophy is indicated by the bluish stripe at the top of the diagram.
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ijms-16-01429-f001: Mice lacking hyperpolarization-activated cyclic nucleotide-gated (HCN) 2+4 channels do not develop a significant prolongation of the action potential during ventricular hypertrophy. (A) Action potentials of ventricular myocytes isolated from control (CTR), hypertrophic control (TACCTR) and hypertrophic HCN2+4 knockout (TACKO) mice. Ventricular hypertrophy was induced by the transverse aortic constriction procedure (TAC); (B) Mean action potential durations (APD) of ventricular myocytes from controls (CTR, white), HCN2+4 knockouts (KO, black), hypertrophic controls (TACCTR, light grey) and hypertrophic HCN2+4 knockouts (TACKO, dark grey). n.s. means p > 0.05, **p < 0.01. (A) and (B) are taken from Hofmann, F. et al. [46]; (C) During ventricular hypertrophy, an increased activity of HCN channels, together with a decrease in potassium currents, counteracts the repolarization of the action potential. The resulting action potential prolongation increases the risk of early after depolarizations (EAD) which are an important cause of lethal ventricular arrhythmias. The diagram is partly based on [61]. If and IK are indicated by red and green stripes, respectivley. The development of ventricular hypertrophy is indicated by the bluish stripe at the top of the diagram.

Mentions: Recently we addressed this issue directly by analyzing pro-arrhythmic parameters in If deficient animals before and after induction of cardiac hypertrophy [46]. The complete loss of If in the working myocardium was achieved by the combined deletion of the predominant ventricular isoforms HCN2 and HCN4. By using this conditional double knockout approach, we were able to demonstrate that the increased If in hypertrophic working myocardium alters the repolarization of the ventricular action potential (Figure 1). This was remarkable since, in analogy to sinoatrial node cells, the depolarizing If current should contribute to the (diastolic) depolarization phase of the ventricular action potential rather than repolarization. However, the involvement of If to ventricular repolarization is explainable by the very slow deactivation kinetic of HCN channels. Because of the relatively fast ventricular cycle length a significant fraction of HCN channels remains activated during the entire cardiac action potential [17,47,48,49]. Such HCN background currents are able to counteract ventricular repolarization in phase 2 and 3 of the action potential in the hypertrophied myocardium, where the expression of If current is increased and simultaneously outward potassium currents are reduced. Our ventricular HCN2/4 knockout model identified the enhanced If as an important contributor to the typical electrophysiological alterations observed in the hypertrophic heart including prolonged ventricular action potentials and lengthened QT (time between start of the Q and end of the T wave) intervals [50]. Considering the fact that delayed ventricular repolarization and prolonged QT intervals promote early after-depolarizations and electrical instability, ventricular HCN channels may play a significant role in the diseased heart by increasing the risk for severe ventricular arrhythmias [51,52].


HCN channels--modulators of cardiac and neuronal excitability.

Herrmann S, Schnorr S, Ludwig A - Int J Mol Sci (2015)

Mice lacking hyperpolarization-activated cyclic nucleotide-gated (HCN) 2+4 channels do not develop a significant prolongation of the action potential during ventricular hypertrophy. (A) Action potentials of ventricular myocytes isolated from control (CTR), hypertrophic control (TACCTR) and hypertrophic HCN2+4 knockout (TACKO) mice. Ventricular hypertrophy was induced by the transverse aortic constriction procedure (TAC); (B) Mean action potential durations (APD) of ventricular myocytes from controls (CTR, white), HCN2+4 knockouts (KO, black), hypertrophic controls (TACCTR, light grey) and hypertrophic HCN2+4 knockouts (TACKO, dark grey). n.s. means p > 0.05, **p < 0.01. (A) and (B) are taken from Hofmann, F. et al. [46]; (C) During ventricular hypertrophy, an increased activity of HCN channels, together with a decrease in potassium currents, counteracts the repolarization of the action potential. The resulting action potential prolongation increases the risk of early after depolarizations (EAD) which are an important cause of lethal ventricular arrhythmias. The diagram is partly based on [61]. If and IK are indicated by red and green stripes, respectivley. The development of ventricular hypertrophy is indicated by the bluish stripe at the top of the diagram.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4307311&req=5

ijms-16-01429-f001: Mice lacking hyperpolarization-activated cyclic nucleotide-gated (HCN) 2+4 channels do not develop a significant prolongation of the action potential during ventricular hypertrophy. (A) Action potentials of ventricular myocytes isolated from control (CTR), hypertrophic control (TACCTR) and hypertrophic HCN2+4 knockout (TACKO) mice. Ventricular hypertrophy was induced by the transverse aortic constriction procedure (TAC); (B) Mean action potential durations (APD) of ventricular myocytes from controls (CTR, white), HCN2+4 knockouts (KO, black), hypertrophic controls (TACCTR, light grey) and hypertrophic HCN2+4 knockouts (TACKO, dark grey). n.s. means p > 0.05, **p < 0.01. (A) and (B) are taken from Hofmann, F. et al. [46]; (C) During ventricular hypertrophy, an increased activity of HCN channels, together with a decrease in potassium currents, counteracts the repolarization of the action potential. The resulting action potential prolongation increases the risk of early after depolarizations (EAD) which are an important cause of lethal ventricular arrhythmias. The diagram is partly based on [61]. If and IK are indicated by red and green stripes, respectivley. The development of ventricular hypertrophy is indicated by the bluish stripe at the top of the diagram.
Mentions: Recently we addressed this issue directly by analyzing pro-arrhythmic parameters in If deficient animals before and after induction of cardiac hypertrophy [46]. The complete loss of If in the working myocardium was achieved by the combined deletion of the predominant ventricular isoforms HCN2 and HCN4. By using this conditional double knockout approach, we were able to demonstrate that the increased If in hypertrophic working myocardium alters the repolarization of the ventricular action potential (Figure 1). This was remarkable since, in analogy to sinoatrial node cells, the depolarizing If current should contribute to the (diastolic) depolarization phase of the ventricular action potential rather than repolarization. However, the involvement of If to ventricular repolarization is explainable by the very slow deactivation kinetic of HCN channels. Because of the relatively fast ventricular cycle length a significant fraction of HCN channels remains activated during the entire cardiac action potential [17,47,48,49]. Such HCN background currents are able to counteract ventricular repolarization in phase 2 and 3 of the action potential in the hypertrophied myocardium, where the expression of If current is increased and simultaneously outward potassium currents are reduced. Our ventricular HCN2/4 knockout model identified the enhanced If as an important contributor to the typical electrophysiological alterations observed in the hypertrophic heart including prolonged ventricular action potentials and lengthened QT (time between start of the Q and end of the T wave) intervals [50]. Considering the fact that delayed ventricular repolarization and prolonged QT intervals promote early after-depolarizations and electrical instability, ventricular HCN channels may play a significant role in the diseased heart by increasing the risk for severe ventricular arrhythmias [51,52].

Bottom Line: The data, which are mainly derived from studies using transgenic mice, suggest that HCN channels contribute significantly to cellular excitability in these tissues.Remarkably, the impact of the channels is clearly more pronounced in pathophysiological states including ventricular hypertrophy as well as neural inflammation and neuropathy suggesting that HCN channels may constitute promising drug targets in the treatment of these conditions.This perspective as well as the current therapeutic use of HCN blockers will also be addressed.

View Article: PubMed Central - PubMed

Affiliation: Institut für Experimentelle und Klinische Pharmakologie und Toxikologie, Friedrich-Alexander-Universität Erlangen-Nürnberg, 91054 Erlangen, Germany. Stefan.Herrmann@pharmakologie.uni-erlangen.de.

ABSTRACT
Hyperpolarization-activated cyclic nucleotide-gated (HCN) channels comprise a family of cation channels activated by hyperpolarized membrane potentials and stimulated by intracellular cyclic nucleotides. The four members of this family, HCN1-4, show distinct biophysical properties which are most evident in the kinetics of activation and deactivation, the sensitivity towards cyclic nucleotides and the modulation by tyrosine phosphorylation. The four isoforms are differentially expressed in various excitable tissues. This review will mainly focus on recent insights into the functional role of the channels apart from their classic role as pacemakers. The importance of HCN channels in the cardiac ventricle and ventricular hypertrophy will be discussed. In addition, their functional significance in the peripheral nervous system and nociception will be examined. The data, which are mainly derived from studies using transgenic mice, suggest that HCN channels contribute significantly to cellular excitability in these tissues. Remarkably, the impact of the channels is clearly more pronounced in pathophysiological states including ventricular hypertrophy as well as neural inflammation and neuropathy suggesting that HCN channels may constitute promising drug targets in the treatment of these conditions. This perspective as well as the current therapeutic use of HCN blockers will also be addressed.

Show MeSH
Related in: MedlinePlus