Limits...
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.

Show MeSH

Related in: MedlinePlus

Mice with a selective deletion of HCN2 in peripheral sensory neurons (snsHCN2KO) display reduced neuropathic pain behavior in response to (A) noxious heat and (B) mechanical stimulation (n = 9–10 mice); (C) Block of HCN channels by intraperitoneal (i.p.) injection of ZD7288 (4 mg/kg) 14 days after nerve injury significantly decreased mechanical hypersensitivity in controls (Ctr), but had no effect in snsHCN2KO (n = 5 mice). All data are presented as relative difference between the injured right and the non-injured left hindpaw ((R − L)/L × 100). PWT and PWL, paw withdrawal threshold and paw withdrawal latency, respectively. *p < 0.05, **p < 0.01. n.s., non significant.
© Copyright Policy
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC4307311&req=5

ijms-16-01429-f002: Mice with a selective deletion of HCN2 in peripheral sensory neurons (snsHCN2KO) display reduced neuropathic pain behavior in response to (A) noxious heat and (B) mechanical stimulation (n = 9–10 mice); (C) Block of HCN channels by intraperitoneal (i.p.) injection of ZD7288 (4 mg/kg) 14 days after nerve injury significantly decreased mechanical hypersensitivity in controls (Ctr), but had no effect in snsHCN2KO (n = 5 mice). All data are presented as relative difference between the injured right and the non-injured left hindpaw ((R − L)/L × 100). PWT and PWL, paw withdrawal threshold and paw withdrawal latency, respectively. *p < 0.05, **p < 0.01. n.s., non significant.

Mentions: HCN channels are widely expressed throughout the peripheral pain pathway. They were found at peripheral and spinal terminals, in the perikaryon as well as along the axon of the DRG neuron [66,68,72,73,74,79,88]. An important site for HCN-mediated hyperexcitability appears to be in the skin and along the axon, since intraplantar as well as perineural administration of ZD7288 significantly reduced neuropathic pain behavior [66,73,86]. It is not clear if presynaptic HCN channels are also involved in the facilitated spinal transmission as a consequence of peripheral nerve injury, because intrathecal administration of ZD7288 produced ambiguous results [70,87] and nonspecific drug effects were suggested [89,90]. Experiments with genetically engineered HCN mutants confirmed the substantial participation of Ih to neuropathic pain and suggested a pivotal role for HCN2 [74,75,77]. Emery et al., demonstrated that conditional deletion of HCN2 abolished pain behavior in the CCI model [77]. We could largely confirm these results in a different model of neuropathy using a virtually identical HCN2 mutant (snsHCN2KO) [74]. Neuropathy was elicited by unilateral transection of the fourth lumbar spinal nerve innervating the lateral back of the foot and parts of the sole. As compared to baseline, heat hyperalgesia in control mice significantly increased until day 7 and then slowly declined, but still remained elevated (p < 0.01, Figure 2A). In contrast, mice with a deletion of HCN2 in nociceptive NaV1.8-expressing neurons (snsHCN2KO) developed no significant hyperalgesic behavior as compared to baseline values. Similar findings were observed with mechanical stimulation. After induction of neuropathy, tactile hypersensitivity developed equally for the first three days in controls and knockouts (Figure 2B). However, mechanical withdrawal thresholds then recovered towards baseline in snsHCN2KOs, but not in controls. Furthermore we could exclude a significant participation of HCN2 channels in other cells or other HCN isoforms, since administration of ZD7288 showed no additional effect in snsHCN2KO mice in line with observations made by Emery et al. [77].


HCN channels--modulators of cardiac and neuronal excitability.

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

Mice with a selective deletion of HCN2 in peripheral sensory neurons (snsHCN2KO) display reduced neuropathic pain behavior in response to (A) noxious heat and (B) mechanical stimulation (n = 9–10 mice); (C) Block of HCN channels by intraperitoneal (i.p.) injection of ZD7288 (4 mg/kg) 14 days after nerve injury significantly decreased mechanical hypersensitivity in controls (Ctr), but had no effect in snsHCN2KO (n = 5 mice). All data are presented as relative difference between the injured right and the non-injured left hindpaw ((R − L)/L × 100). PWT and PWL, paw withdrawal threshold and paw withdrawal latency, respectively. *p < 0.05, **p < 0.01. n.s., non significant.
© Copyright Policy
Related In: Results  -  Collection

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

ijms-16-01429-f002: Mice with a selective deletion of HCN2 in peripheral sensory neurons (snsHCN2KO) display reduced neuropathic pain behavior in response to (A) noxious heat and (B) mechanical stimulation (n = 9–10 mice); (C) Block of HCN channels by intraperitoneal (i.p.) injection of ZD7288 (4 mg/kg) 14 days after nerve injury significantly decreased mechanical hypersensitivity in controls (Ctr), but had no effect in snsHCN2KO (n = 5 mice). All data are presented as relative difference between the injured right and the non-injured left hindpaw ((R − L)/L × 100). PWT and PWL, paw withdrawal threshold and paw withdrawal latency, respectively. *p < 0.05, **p < 0.01. n.s., non significant.
Mentions: HCN channels are widely expressed throughout the peripheral pain pathway. They were found at peripheral and spinal terminals, in the perikaryon as well as along the axon of the DRG neuron [66,68,72,73,74,79,88]. An important site for HCN-mediated hyperexcitability appears to be in the skin and along the axon, since intraplantar as well as perineural administration of ZD7288 significantly reduced neuropathic pain behavior [66,73,86]. It is not clear if presynaptic HCN channels are also involved in the facilitated spinal transmission as a consequence of peripheral nerve injury, because intrathecal administration of ZD7288 produced ambiguous results [70,87] and nonspecific drug effects were suggested [89,90]. Experiments with genetically engineered HCN mutants confirmed the substantial participation of Ih to neuropathic pain and suggested a pivotal role for HCN2 [74,75,77]. Emery et al., demonstrated that conditional deletion of HCN2 abolished pain behavior in the CCI model [77]. We could largely confirm these results in a different model of neuropathy using a virtually identical HCN2 mutant (snsHCN2KO) [74]. Neuropathy was elicited by unilateral transection of the fourth lumbar spinal nerve innervating the lateral back of the foot and parts of the sole. As compared to baseline, heat hyperalgesia in control mice significantly increased until day 7 and then slowly declined, but still remained elevated (p < 0.01, Figure 2A). In contrast, mice with a deletion of HCN2 in nociceptive NaV1.8-expressing neurons (snsHCN2KO) developed no significant hyperalgesic behavior as compared to baseline values. Similar findings were observed with mechanical stimulation. After induction of neuropathy, tactile hypersensitivity developed equally for the first three days in controls and knockouts (Figure 2B). However, mechanical withdrawal thresholds then recovered towards baseline in snsHCN2KOs, but not in controls. Furthermore we could exclude a significant participation of HCN2 channels in other cells or other HCN isoforms, since administration of ZD7288 showed no additional effect in snsHCN2KO mice in line with observations made by Emery et al. [77].

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