HCN channels : Function and clinical implications

Eduardo E. Benarroch
Neurology 2013;80;304
DOI 10.1212/WNL.0b013e31827dec42

This information is current as of January 16, 2013

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CLINICAL
IMPLICATIONS OF
NEUROSCIENCE
HCN channels
RESEARCH
Function and clinical implications
Section Editor
Eduardo E.
Benarroch, MD

Eduardo E. Benarroch, The hyperpolarization-activated cyclic nucleotide-gated contains the cyclic nucleotide-binding domain (CNBD),
MD (HCN) channels belong to the superfamily of pore-loop which mediates modulation by cyclic nucleotides. A
cation channels. In mammals, the HCN channel family highly conserved asparagine residue in the extracellular
comprises 4 members (HCN1–4) that are expressed in loop between S5 and the pore loop is glycosylated; this
Correspondence to
Dr. Benarroch: heart and nervous system. HCN channels are activated posttranslational channel modification is crucial for nor-
benarroch.eduardo@mayo.edu by membrane hyperpolarization, are permeable to Na1 mal cell surface expression.
and K1, and are constitutively open at voltages near the
Heterogeneity and distribution of HCN channels. There are
resting membrane potential. In many cases, activation is
4 homologous HCN channel subunits (HCN1–4) in
facilitated by direct interaction with cyclic nucleotides,
mammals. These subunits form different homotetramers
particularly cyclic adenosine monophosphate (cAMP).
or heterotetramers with distinct biophysical properties
The cation current through HCN channels is known as
(table 1).1,2 HCN1 is expressed in the neocortex, hippo-
Ih; opening of HCN channels elicits membrane depo-
campus, brainstem, spinal cord, and dorsal root ganglion
larization toward threshold for action potential genera-
(DRG); HCN2 is distributed nearly ubiquitously, with
tion, and reduces membrane resistance and thus the
the highest expression in the thalamus, brainstem nuclei,
magnitude of excitatory and inhibitory postsynaptic po-
and small nociceptive DRG neurons; HCN3 is expressed
tentials. HCN channels have a major role in controlling
at very low levels in the CNS, except the olfactory bulb
neuronal excitability, dendritic integration of synaptic
and hypothalamus; and HCN4 is strongly expressed in
potentials, synaptic transmission, and rhythmic oscilla-
thalamic nuclei and the olfactory bulb.11 In neurons,
tory activity in individual neurons and neuronal net-
HCN channels are expressed in dendrites and axon
works. These channels participate in mechanisms of
terminals, in some cases with a heterogeneous distribu-
synaptic plasticity and memory, thalamocortical rhythms,
tion. For example, in neocortical and CA1 hippocampal
and somatic sensation. Experimental evidence indicates
pyramidal and thalamic reticular neurons, there is a gra-
that HCN channels may also contribute to mechanisms
dient of HCN1 expression, with higher expression in the
of epilepsy and pain. The physiologic functions of HCN
distal dendrites than in the soma12,13; in layer 5 neocor-
channels and their implications for neurologic disorders
tical pyramidal neurons, HCN1 is predominantly ex-
have been recently reviewed.1–10
pressed in dendrites, whereas HCN2 is expressed in the
soma. All 4 HCN channel isoforms, particularly HNC4
HCN CHANNELS AND IH CURRENT Structure of HCN
and to a lesser extent HCN2, are expressed in the heart.
channels. The HCN channels form the subgroup of
cyclic nucleotide-gated cation channels within the large Activation of HCN channels and Ih current. The HCN
superfamily of the pore-loop cation channels. Like other channels are permeable to Na1 and K1 and conduct a
pore-loop channels, HCN channels are complexes con- mixed cation current, Ih. The ratio of the Na1 to K1
sisting of 4 subunits that are arranged around the central permeability of the channel ranges from 1:3 to 1:5, yield-
pore. Each HCN channel subunit consists of 3 principal ing values for the reversal potential between 225 and
structural modules: the transmembrane core and the 240 mV. As a consequence, activation of Ih at resting
cytosolic amino (N)-terminal and carboxy (C)-terminal membrane potentials depolarizes the membrane toward
domains (figure).1 The transmembrane core is com- threshold for firing of action potentials.1,7 An increase in
posed of 6 transmembrane segments (S1–S6) including extracellular K1 concentration strongly increases current
a positively charged voltage sensor (S4) and the ion- amplitude.1 Membrane hyperpolarization is necessary
conducting pore region between S5 and S6. The prox- and sufficient to activate the HCN channels; cyclic
imal portion of the cytosolic C-terminal domain nucleotides such as cAMP act as costimulatory modu-
GLOSSARY
cAMP 5 cyclic adenosine monophosphate; CNBD 5 cyclic nucleotide-binding domain; DRG 5 dorsal root ganglion; EPSP 5
excitatory postsynaptic potentials; HCN 5 hyperpolarization-activated cyclic nucleotide-gated; LTP 5 long-term potentia-
tion; PGE2 5 prostaglandin E2; PIP2 5 phosphatidylinositol 4,5-bisphosphate; SA 5 sinoatrial.

From the Department of Neurology, Mayo Clinic, Rochester, MN.

Go to Neurology.org for full disclosures. Funding information and disclosures deemed relevant by the authors, if any, are provided at the end of the article.

304 © 2013 American Academy of Neurology

ª 2013 American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

 Figure Structure and functions of hyperpolarization-activated cyclic nucleotide-gated channels

The hyperpolarization-activated cyclic nucleotide-gated (HCN) channels belong to the superfamily of pore-loop cation channels.
HCN channels are complexes consisting of 4 subunits that are arranged around the central pore. Each subunit consists of a trans-
membrane core and the cytosolic amino (N)-terminal and carboxy (C)-terminal domains. The transmembrane core is composed of 6
transmembrane segments (S1–S6) including a positively charged voltage sensor (S4) and the ion-conducting pore region between
S5 and S6. The proximal portion of the cytosolic C-terminal domain contains the cyclic nucleotide-binding domain (CNBD), which
mediates modulation by cyclic nucleotides, such as cyclic adenosine monophosphate (cAMP). The HCN channels are permeable to
Na1 and K1 and conduct a mixed cation current, Ih. Membrane hyperpolarization is necessary and sufficient to activate the HCN
channels; cAMP act as costimulatory modulators that facilitate voltage-dependent HCN channel activation.

lators that facilitate voltage-dependent HCN channel
activation by shifting the voltage dependence of activa-
tion to more positive voltages. Binding of cAMP to the
CNBD induces a conformational change that removes a
tonic inhibition conferred by this domain on channel
opening. Within the HCN channel family, HCN1 is
the subtype with the fastest kinetics and weakest mod-
ulation by cAMP; both HCN2 and HCN4 are strongly
modulated by cAMP.1
Regulation of HCN channels. HCN channels are tightly
regulated by interacting proteins and ions in the cytosol
and the extracellular space.1 HCN channel activity and
regulation occurs at multiple levels, dependent on the
number and subtype of HCN subunits expressed on the
plasma membrane, distribution of HCN channel sub-
units in distinct subcellular compartments, and biophys-
ical properties of the channel (such as voltage-activation
profile and kinetics).1 Intracellular HCN channel mod-
ulators include phosphatidylinositol 4,5-bisphosphate
(PIP2), which acts as an allosteric activator,14 and intra-
cellular protons, which slow down the speed of channel
opening. The protective action of carbonic anhydrase
inhibitors in generalized seizures has been attributed to
the high sensitivity of HCN channels to intracellular
pH. The HCN channels are also the target of phospho-
rylation by different protein kinases. Many neurotrans-
mitters affect HCN channel function by affecting levels
of cAMP or PIP2. For example, in cardiac sinoatrial (SA)
cells, norepinephrine, acting via b1 adrenoceptor,
increases cAMP production and Ih, leading to increased
rate of spontaneous depolarization (and thus heart rate).
In contrast, in dendritic spines prefrontal pyramidal neu-
rons, norepinephrine acting via a2A receptors inhibits
cAMP production and HCN activity.15
HCN channels are macromolecular protein com-
plexes that contain auxiliary proteins required for the
fine-tuning of their electrophysiologic properties, func-
tional coupling to signaling pathways, and trafficking
to specific cellular compartments.1 These proteins
include the MinK-related protein MiRP1 and several
scaffold proteins such as TPR-containing Rab8b inter-
acting protein (TRIP8b), which colocalizes with HCN1
in dendrites of cortical and hippocampal pyramidal cells.1
PHYSIOLOGIC ROLE OF HCN CHANNELS AND IH
CURRENT The unique properties of HCN channels
and Ih make them versatile regulators of neuronal excit-
ability and activity of neuronal networks1,6,7 (table 2).
Setting of the membrane potential. HCN channels are par-
tially open at rest at subthreshold potentials; Ih depolar-
izes the cell and maintains the membrane potential near
the resting membrane potential. Because Ih is partially
activated at physiologic, “resting” conditions, it serves as
a feedback mechanism that counteracts both membrane

Neurology 80 January 15, 2013 305

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 Table 1 HCN channel subtypes

HCN1 HCN2 HCN3 HCN4

Inactivation kinetics Fast Intermediate Slow Slow

cAMP modulation Weakest Strong Weak Strongest

CNS expression Neocortex Ubiquitous Olfactory bulb Thalamus

Hippocampus Hypothalamus Basal ganglia

Brainstem Retinal cones Olfactory bulb

DRG expression Large neurons Nav1.8 expressing — —

nociceptive neurons

Cold-sensitive neurons

Cardiac expression SA node Ubiquitous Cardiac muscle SA bode

AV node AV node

Purkinje system

Knockout mouse Enhanced hippocampal-dependent Ataxia Increased T-wave Embryonic lethal phenotype
phenotype learning and memory amplitude (bradycardia and absent
pacemaker cells)

Impaired motor learning Absence epilepsy Sinus pauses, bradycardia,

and heart block

Epilepsy Reduced inflammatory

and neuropathic pain

Altered color vision Sinus arrhythmia

Reduced cold allodynia

Clinical correlations Increased level and dendric HCN2 mutation causing Ih HCN4 mutation:
expression in granule cells of augmentation associated bradycardia, SA
the dentate gyrus in resected with GEFS1 and AV conduction
hippocampi in TLE impairment, QT
prolongation, syncope

Oxaliplatin-induced cold allodynia?

Abbreviations: AV 5 atrioventricular; cAMP 5 cyclic adenosine monophosphate; DRG 5 dorsal root ganglion; GEFS 5 generalized epilepsy with febrile
seizures plus; HCN 5 hyperpolarization-activated cyclic nucleotide-gated; SA 5 sinoatrial; TLE 5 temporal lobe epilepsy.

hyperpolarization and depolarization. Thus, HCN chan-
nels may have excitatory, inhibitory, or modulatory func-
tions.7 HCN channels interact with other ion channels
that influence the membrane potential. For example, the
delayed-rectifier M-type K1 channels (Kv7 or KCNQ
channel) have a large effect on HCN function, as they
determine whether HCN channels act in an excitatory or
inhibitory fashion.16 The tonic depolarizing effect of Ih
increases the steady-state inactivation of low-threshold
voltage-gated calcium (Ca21) channels (T-channels)
and thus restrict the genesis of dendritic Ca21 spikes.17
Dampening of synaptic potentials. According to Ohm’s
law, the magnitude of voltage change of the membrane
is proportional to its input resistance. As HCN opening
reduces the input resistance of the membrane, Ih damp-
ens the amplitude and duration of both excitatory post-
synaptic potentials (EPSP) and inhibitory postsynaptic
potentials.6,17 In some neurons, the depolarizing effects
of Ih may counterbalance its dampening effect on EPSP
triggered by glutamate receptor activation. In many cells,
such as those in the subthalamic nucleus, the main effect
of Ih is to antagonize the hyperpolarizing inhibitory in-
puts mediated by GABAA receptors.17
Dendritic integration. Dendritic integration is crucial for
signal processing in most neurons. Since individual EPSP
are too small to reach the action potential threshold,
generation of action potentials at the soma requires the
integration of multiple excitatory synaptic inputs. The
presence of constitutively open Ih channels in dendrites
influences the passive propagation of EPSP by lowering
membrane resistance and reducing their amplitude.
HCN1 channels participate in dendritic integration of
EPSP in neocortical and CA1 pyramidal neurons.17 In
these neurons, the density of Ih is higher in distal than in
the proximal dendrites, and therefore temporal summa-
tion is more dampened for distal than for proximal
inputs propagating to the soma; this somatoden-
dritic gradient of HCN expression allows for the effects
of excitatory synaptic inputs to becomes independent of
their location.12 Activated HCN channels also participate
in the detection of coincident synaptic inputs, suppress-
ing the summation of EPSP that occur at low frequency
and improving the selectivity for synchronous synaptic
inputs.18
Neuronal and network oscillations. Sustained rhythmic
oscillations are a hallmark feature of neuronal circuits

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 Table 2 Physiologic effects of HCN channel and Ih

Function Ih property Physiologic implications

Maintenance of Constitutively open at voltages near RMP Voltage-dependent Ih activation and deactivation act as negative feedback that
RMP opposes Vm deviations from RMP

Elicit membrane depolarization Reduces amplitude of EPSP or IPSP

Lower membrane resistance

Dendritic Somatodendritic gradient of Ih expression in hippocampal and Affects temporal summation of EPSP
integration neocortical neurons

Increase spatial Interactions of HCN1 with a2A adrenoreceptors in dendritic a2A Receptor-mediated inhibition of cAMP reduces Ih and increases efficacy of
working memory spines of prefrontal neurons excitatory inputs to prefrontal neurons

Impaired High HCN1 expression in distal dendrites of CA1 neuron Ih in distal dendrites inhibits Ca21 spikes triggered by activation of glutamate
hippocampal LTP receiving inputs from the entorhinal cortex receptors, thus reducing LTP at the perforant pathway–CA1 synapse

Motor learning HCN1 mediates a depolarizing current in spontaneously By counteracting the hyperpolarizing effects of inhibitory inputs, Ih enables
spiking Purkinje cells Purkinje cells to maintain a high-frequency input–output relationship

Neuronal HCN1 expression in hippocampus Promotes hippocampal u oscillations (4–6 Hz)

oscillations

HCN2 expression in TC neurons Ih promotes burst-firing mode in TC neurons through interactions with T currents

HCN2 deficiency leads to spike-and-wave discharge by increasing number of

closed T channels available to activation by depolarizing stimuli

Thalamocortical GABAergic inputs from the thalamic reticular nucleus elicit Via interactions with T currents, Ih promotes rhythmic burst firing in TC neurons
network oscillations rhythmic IPSP that activate Ih in TC neurons and spindle oscillation during non-REM sleep

Persistent activation of Ih in TC neurons responsible for the silent period

between spindle waves

Abbreviations: EPSP 5 excitatory postsynaptic potentials; HCN 5 hyperpolarization-activated cyclic nucleotide-gated; IPSP 5 inhibitory postsynaptic
potentials; LTP 5 long-term potentiation; RMP 5 resting membrane potential; TC 5 thalamocortical; Vm 5 membrane potential.

in various brain regions including the thalamus, hippo-
campus, and neocortex. HCN channels have an impor-
tant role in oscillatory properties of individual neurons
and networks. Typical examples are u oscillations in
hippocampal circuits19 and slow and spindle oscillation
in thalamocortical circuits.20 There are also several
studies that demonstrated the importance of Ih for g
oscillations in the hippocampus, synchronized oscilla-
tions in the inferior olive, and subthreshold oscillations
in the entorhinal cortex.1
PHYSIOLOGIC IMPLICATIONS HCN channels may
have an important role in mechanisms of thalamocorti-
cal oscillations, hippocampal plasticity, spatial working
memory, motor learning, and nociception (table 2).
Generation of thalamic rhythms. Ih is involved in slow (d)
frequency single-cell oscillations in thalamic relay (thal-
amocortical) neurons; synchronized thalamocortical net-
work oscillations at d and spindle frequency during
non-REM sleep; and generalized spike-and-wave dis-
charges associated with absence seizures.1,6 Thalamocor-
tical neurons fire in 2 distinct firing modes: transmission
mode and burst mode. During wakefulness and REM
sleep, thalamocortical neurons are depolarized by affer-
ent inputs and fire in a transmission of “single spike”
mode; burst firing mode occurs when thalamocortical
neurons are hyperpolarized and is characteristically seen
during non-REM sleep or absence seizures. Thalamic
neurons fire in the “burst mode” through the interaction
of Ih and a low-threshold Ca21 current (T-current). The
activation of Ih by hyperpolarization beyond 265 mV
slowly depolarizes the membrane potential until a
rebound low-threshold Ca21 spike is generated by
T-channel activation, leading to the discharge of a burst
of action potentials. Depolarization inactivates both
HCN and T channels, leading to termination of the
spike. This is followed by a hyperpolarizing “overshoot”
that activates Ih, leading to repetition of the cycle and
continuous rhythmic burst firing. These single-cell oscil-
lations are synchronized in large neuronal circuits and
can be recorded in the EEG as d waves during non-
REM sleep. Electrophysiologic recordings in thalamic
slice preparations of HCN2-deficient mice revealed that
the current produced by HCN2 constitutes the major
component underlying thalamocortical Ih.21 Deletion of
HCN2 results in hyperpolarizing shift of the resting
membrane potential in thalamocortical neurons, result-
ing in higher susceptibility of these neurons to fire in the
burst mode in response to excitatory inputs as compared
with wild-type neurons. This altered thalamic firing
behavior of HCN2-deficient mice manifests with
spike-and-wave discharges, the hallmark of absence
epilepsy.20
Ih is also involved in the generation of the synchro-
nized thalamocortical network oscillations that underlie
spindle waves on surface EEG during N2 stage of non-
REM sleep. In this state, burst firing in thalamic retic-
ular neurons induces rhythmic inhibitory postsynaptic
potentials in thalamocortical cells; this hyperpolarization

Neurology 80 January 15, 2013 307

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 activates Ih and removes inactivation of the low-threshold
Ca21 currents, resulting in burst firing in thalamocor-
tical neurons, which re-excites the thalamic reticular
neurons and stimulates cortical pyramidal cells. Net-
work synchronization between the cortex and the
thalamus leads to nearly simultaneous occurrence of
spindle waves over widespread areas of the cortex.22
Learning and memory mechanisms. Mice with selective
HCN1 gene deletions have better hippocampal-
dependent spatial learning and memory than do wild-
type mice; this reflects enhanced long-term poten-
tiation (LTP) at the synapse between the entorhinal
cortex and CA1 and increased excitability of CA1 den-
drites.23 This suggests that HCN1 channels inhibit den-
dritic integration and synaptic long-term plasticity at the
perforant path inputs to the distal dendrites of CA1
pyramidal neurons; the high HCN1 expression at this
level may interfere with generation of Ca21 spikes, a
process that is critical for the induction of LTP at den-
dritic synapses.1
HCN channels are also involved in mechanisms of
spatial working memory in the prefrontal cortex. In den-
dritic spines of prefrontal neurons, HCN channels coloc-
alize and functionally interact with a2A adrenoceptors,
which are activated by relatively low levels of norepi-
nephrine released during alert and wakefulness.15 Acti-
vation of a2A adrenoceptors inhibits the production of
cAMP and thus reduces the open probability of HCN
channels, leading to increased membrane resistance; this
would increase the efficiency of excitatory synaptic
inputs to the dendrites of prefrontal neurons engaged
in a specific task.1
HCN1 channels also participate in cerebellar mecha-
nisms of motor learning. HCN1 deletion causes pro-
found deficits in tests that require complex and
repeated coordination of motor output by the cere-
bellum.24 The HCN1 channels are expressed in Pur-
kinje cells; in these spontaneously spiking neurons,
the depolarizing effects of Ih counteract the effects of
inhibitory (hyperpolarizing) inputs. This mechanism
would allow Purkinje to maintain a constant input-
output relationship independently of the effects of
previous inputs to the cerebellum.
Somatic sensation. Many DRG neurons express HCN
channels. Large, non-nociceptive DRG neurons with
large myelinated (Ab) axons and a small population
of cold-sensitive DRG neurons express HCN1, which
is relatively insensitive to cAMP. In contrast, nocicep-
tive DRG neurons with small myelinated (Ad) or
unmyelinated (C) axons express HCN2, which is
responsible for a slower and cAMP-sensitive in Ih cur-
rent.25 In nociceptive neurons, HCN2 expression has
an important role in modulating the generation of
action potentials in response to inflammatory
308 Neurology 80 January 15, 2013
ª 2013 American Academy of Neurology. Unauthorized reproduction of this article is prohibited.
mediators such as prostaglandin E2 (PGE2), which
increase cAMP production.26
Cardiac rhythm. Although not directly related to neural
function, control of cardiac rhythm is critical to maintain
cardiac output and cerebral perfusion and is controlled
by autonomic influences on HCN channels expressed
by SA node cells and the cardiac conduction system.
Ih was initially described as “pacemaker current,” as it
has a prominent role in the progressive diastolic depo-
larization of SA cells that drives their membrane toward
threshold of Ca21 channel activation following repo-
larization.1 HCN4 makes up ;80% and HCN2
;20% of SA node Ih. Sympathetic stimulation acceler-
ates heart rate via b-adrenoceptor-triggered cAMP pro-
duction and Ih activation, whereas low level vagal
stimulation lowers heart rate via inhibition of cAMP
synthesis. Adult HCN4 knockout mice have cardiac
arrhythmia characterized by recurrent sinus pauses.
CLINICAL CORRELATIONS Only 4 inherited HCN
channel mutations have been described; all are localized
in the HCN4 gene and are associated with sinus brady-
cardia. So far, disease-causing mutations in human
HCN1–3 genes have not been reported. Acquired
HCN1 and HCN2 channels dysfunction has been
linked with epilepsy, necropathic pain, and subarach-
noid hemorrhage.
Epilepsy. Given the complex effects of Ih in fine-tuning
cellular excitability, synaptic responses, and network
activity, it is not surprising that abnormal regulation of
HCN expression or function has been implicated in
epilepsy.6 However, the role of HCN dysregulation in
epilepsy is complex. Studies in experimental models
indicate that both upregulation and downregulation of
HCN channels can be associated with seizures; different
HCN types may contribute to different extents to focal
or generalized epilepsy syndromes; and the role of HCN
channels strongly depends on cellular localization and
physiologic context.5,6,27 Furthermore, the results on
experimental epilepsy models may not necessarily be
applicable to human epilepsy syndromes.
HCN channel abnormalities in the epileptic brain
can manifest as altered mRNA and protein expression,
subcellular distribution, biophysical properties, and spa-
tial selectivity and temporal pattern of dysregulation fol-
lowing seizures.6 Altered HCN1 or HCN2 expression
(i.e., transcriptional channelopathy) has been demon-
strated in hippocampus of patients with severe temporal
lobe epilepsy as well as in animal models of temporal
lobe and absence epilepsies.6,28–30 These changes may not
necessarily be the cause but rather represent compensa-
tory responses to abnormal excitability during seizures.
In organotypic hippocampal slice cultures, seizure-
like events selectively reduced HCN1 and increased
 HCN2 mRNA levels.31 Loss of HCN1 expression is
associated with higher seizure severity and higher
seizure-related mortality in mouse models of limbic
seizures.28 For example, adult HCN1 null mice are more
susceptible to kainic acid–induced seizures; this is
accompanied by increased spontaneous activity,
increased dendric excitability, and imbalance between
normal excitatory and inhibitory synaptic activity.29
Electrophysiologic recording in vitro from layers II/III of
neocortex resected from patients with temporal or fron-
tal lobe epilepsy suggests a deficit of HCN1 subunits in
the human epileptogenic neocortex, which in turn may
increase excitability and probability of seizure activity.30
However, there is also evidence for enhanced HCN1
expression and dendritic localization in surviving granule
cells of the dentate gyrus in resected hippocampi from
patients with temporal lobe epilepsy and in experimental
temporal lobe seizure models7; in these conditions,
increased Ih in the dentate gyrus may represent a com-
pensatory mechanism to reduce neuronal
hyperexcitability.32
Inherited cortical HCN1 channel loss also amplifies
dendritic Ca21 electrogenesis and burst firing in a rat
absence epilepsy model.33 In contrast, increased HCN1
activity in thalamocortical neurons, leading impaired
control of the shift from burst to tonic firing, has been
found in a genetic rat model of absence epilepsy.22
The role of HCN2 channels in epilepsy is also incom-
pletely understood. Spontaneous HCN2 mutations lead-
ing to markedly reduced HCN2 expression has been
linked to generalized spike-wave absence seizures in
mice.21,34 A recessive loss-of-function mutation of the
HCN2 has also been linked to human generalized epi-
lepsy.35 However, screening in subjects with febrile seiz-
ures and genetic epilepsy with febrile seizures plus
revealed that 2.4% (as opposed to 0.2% of controls)
carried a common triple proline deletion HCN2, result-
ing in a gain of function of HCN2-mediated Ih.32
Pain. Several findings in experimental models of inflam-
matory or neuropathic pain suggest HCN channels, par-
ticularly HCN2, have a prominent role in both
inflammatory and neuropathic pain.1,2,25 Experimental
nerve injury results in increased Ih currents; pharmaco-
logic blockade of HCN channels by the pan-HCN
inhibitor, ZD-7288, reverses both pain behavior and
the spontaneous discharges in injured nerve fibers and
gives significant analgesia in a variety of pain models.2,25
There is evidence that HCN2 has a prominent role in
mediating enhanced sensitivity to heat, cold, or mechan-
ical stimuli in both inflammatory and neuropathic
pain.5,27 Selective HCN2 deletion restricted to the
Nav1.8-expressing nociceptive DRG neurons pre-
vents heat hyperalgesia triggered by proinflamma-
tory stimuli such as PGE2. Selective knockout
studies indicate that HCN1 channels may also have
ª 2013 American Academy of Neurology. Unauthorized reproduction of this article is prohibited.
a contributory role in cold hyperalgesia and allo-
dynia in the setting of nerve injury or oxaliplatin-
induced neuropathy.36
Subarachnoid hemorrhage. Disruption of ionic homeosta-
sis and neuronal hyperexcitability contribute to early
brain injury after subarachnoid hemorrhage. Whole-cell
recordings in rat brain slices indicate that perfusion of
hemoglobin-containing artificial CSF produced neuro-
nal hyperexcitability and inhibited HCN currents in
CA1 pyramidal neurons by scavenging nitric oxide.37
PERSPECTIVE HCN channels are important regula-
tors of neuronal excitability and network activity in the
nervous system. Given the evidence of their potential role
in epilepsy and pain, these channels provide an attractive
therapeutic target. Whereas HCN4 agonists, such as
ivabradine, provide an alternative to b-blockers or calci-
um channel blockers for treatment of tachycardia,2 ago-
nists or antagonists of HCN1 and HCN2 are not yet
available for clinical use. Whereas selective HCN2 block-
ers could be used to treat neuropathic pain, the complex
and diverse role of HCN1 and HCN2 in epilepsy may
prove challenging, as both inhibition and activation of Ih
may be beneficial depending on the type of epilepsy.
Some currently available antiepileptic drugs such as lam-
otrigine increase Ih in dendrites of pyramidal cells.38
DISCLOSURE
The author reports no disclosures relevant to the manuscript. Go to
Neurology.org for full disclosures.
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 HCN channels : Function and clinical implications
Eduardo E. Benarroch
Neurology 2013;80;304
DOI 10.1212/WNL.0b013e31827dec42
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