Accepted Manuscript Title: Neurophysiology of HCN channels: From cellular functions to multiple regulations Author: Chao. He Fang. Chen Bo. Li Zhian. HuTel.: +86 23 68752253. PII: DOI: Reference:
S0301-0082(13)00101-9 http://dx.doi.org/doi:10.1016/j.pneurobio.2013.10.001 PRONEU 1300
To appear in:
Progress in Neurobiology
Received date: Revised date: Accepted date:
23-11-2012 1-10-2013 7-10-2013
Please cite this article as: He, Co., Chen, Fg., Li, Bo., Hu, Zn.,Neurophysiology of HCN channels: from cellular functions to multiple regulations, Progress in Neurobiology (2013), http://dx.doi.org/10.1016/j.pneurobio.2013.10.001 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
Neurophysiology of HCN channels: from cellular functions to multiple regulations
ip t
Chao. Hea, Fang. Chena,*, Bo. Lia, b, Zhian. Hua,*
Department of Physiology, Third Military Medical University, Chongqing 400038, PR China
b
Department of Neurosurgery, Jinan General Military Hospital, Jinan, 250031, PR China
us
*
cr
a
Corresponding author at: Department of Physiology, Third Military Medical University,
an
Chongqing 400038, PR China. Tel: +86 23 68752253 (Fang. Chen) or +86 23 68752254 (Zhian. Hu).
M
E-mail address: [email protected] or [email protected]
Abstract
te
d
Hyperpolarization-activated cyclic nucleotide-gated (HCN) cation channels are encoded by HCN1-4 gene family and have four subtypes. These channels are activated upon
Ac ce p
hyperpolarization of membrane potential and conduct an inward, excitatory current Ih in the nervous system. Ih acts as pacemaker current to initiate rhythmic firing, dampen dendritic
excitability and regulate presynaptic neurotransmitter release. This review summarizes recent insights into the cellular functions of Ih and associated behavior such as learning and memory, sleep and arousal. HCN channels are excellent targets of various cellular signals to finely regulate neuronal responses to external stimuli. Numerous mechanisms, including transcriptional control, trafficking, as well as channel assembly and modification, underlie HCN channel regulation. In the next section, we discuss how the intracellular signals, especially recent findings concerning protein kinases and interacting proteins such as cGKII, Ca2+/CaMKII and TRIP8b, regulate function
1
Page 1 of 120
and expression of HCN channels, and subsequently provide an overview of the effects of neurotransmitters on HCN channels and their corresponding intracellular mechanisms. We also
directions in this exciting area of ion channel research is provided.
ip t
discuss the dysregulation of HCN channels in pathological conditions. Finally, insight into future
cr
Key words: Ih, HCN channels, HCN channels trafficking, extracellular molecules, protein kinases,
us
TRIP8b.
an
Contents
M
1. Introduction
2. Structure and distribution of HCN channels
te
d
3. The effects of Ih on membrane properties and associated physiological functions 3.1. Role of Ih in neuronal soma and proximal dendrites
Ac ce p
3.1.1. Ih in controlling resting membrane potential 3.1.2. Ih in neuronal oscillation
3.2. Role of Ih in distal dendrites 3.3. Role of Ih in presynaptic terminals
4. Regulation of HCN channel function 4.1. Regulation of HCN channels by intracellular molecules 4.1.1. Small molecules 4.1.2. Protein kinases 4.1.3. Interacting proteins
2
Page 2 of 120
4.2. Regulation of HCN channels by extracellular neurotransmitters 4.2.1. Acetylcholine 4.2.2. Monoaminergic neurotransmitters
ip t
4.2.3. Glutamate
cr
4.2.4. Purinergic neurotransmitters
4.2.6. Neuropeptides
an
4.3. Regulation of HCN channels during development
us
4.2.5. Nitric oxide
5. Dysregulation of HCN channels is involved in pathological conditions
M
5.1. Epilepsy
te
5.3. Parkinsonian disease
d
5.2. Neuropathic pain
5.4. Age-related working memory decline
Ac ce p
6. Future perspectives References
Acknowledgments
1. Introduction
The hyperpolarization-activated current, Ih, was first observed in sino-atrial node tissue in 1976 and later was identified in rod photoreceptors and hippocampal pyramidal neurons (Bader et al., 1979; Halliwell and Adams, 1982; Noma and Irisawa, 1976). Due to its unique properties,
3
Page 3 of 120
particularly the activation upon hyperpolarization of the membrane potential, Ih has been also termed If (f for funny) or Iq (q for queer). The hyperpolarization-activated cyclic nucleotide-gated (HCN) cation ion channels underlying Ih were discovered in the late 1990s and subsequently, the
ip t
genes encoding these channels were identified, which enable the expression of HCN channels in
cr
heterologous systems (Ludwig et al., 1998; Ludwig et al., 1999; Santoro et al., 1998; Seifert et al.,
us
1999).
Unlike most other voltage-gated channels, the activation of HCN channels is controlled through
an
dually interdependent membrane potentials and cAMP binding (Kusch et al., 2010; Wu et al., 2011). HCN channels are activated upon hyperpolarization of the membrane potential with
M
sigmoidal kinetics, and this process is facilitated through cAMP, which directly interacts with the channel proteins. These channels do not exhibit voltage-dependent inactivation, and opening
te
d
HCN channel allows the permeability of K + and Na+ ions for the generation of the inward current Ih in the nervous system (Biel et al., 2009; Wahl-Schott and Biel, 2009). Ih contributes to diverse
Ac ce p
neuronal functions, including the determination of resting membrane potential (RMP), generation of neuronal oscillation, and regulation of dendritic integration and synaptic transmission, and is implicated in multiple physiological processes, such as sleep and arousal, learning and memory, and sensation and perception. In the nervous system, the functional properties and expression of HCN channels are diversified to adapt to the corresponding physiological roles, due to the dynamic and precise regulation of these channels through a wide range of cellular signals. The regulation of HCN channels involves short-term regulation through cellular metabolites that directly interact with these channels or protein kinases that induce phosphorylation of channel proteins, and long-term regulation via the regulation of channel
4
Page 4 of 120
expression, heteromerization or subcellular redistribution. In this review, we provide a brief up-to-date summary of the biophysical properties, structure and distribution patterns of HCN channels in the nervous system. These aspects of HCN channels
ip t
have been well reviewed, and more detailed information can be obtained from several excellent
cr
prior publications (Wahl-Schott and Biel, 2009; Robinson and Siegelbaum, 2003; Postea and Biel,
us
2011). Accordingly, we focus on the recent insights into the effects of Ih on membrane properties, the associated physiological functions, and regulation mechanisms underlying HCN channels.
an
Finally, we provide an overview of the dysfunction of HCN channels and corresponding cellular mechanisms in pathological conditions with the goal of identifying the role of dysregulated HCN
M
channels in the pathogenesis of several diseases.
te
d
2. Structure and distribution of HCN channels
Ac ce p
HCN channels belong to the superfamily of voltage-gated pore loop channels with four
pore-forming subunits (HCN1-4) encoded by the HCN1-4 gene family in mammals (Robinson and Siegelbaum, 2003). Each subunit has six transmembrane helices (S1-S6), with the positively charged voltage sensor (S4) and the pore region carrying the GYG motif between S5 and S6, which forms the ion selectivity filter (Macri et al., 2012). Following S6 is the 80-residue C-linker comprising six -helices (A’-F’) and the cyclic nucleotide-binding domain (CNBD). The CNBD consists of three -helices (A-C) and a β-roll between the A- and B-helices (Fig. 1) (Biel et al., 2009; Wahl-Schott and Biel, 2009; Wicks et al., 2011). Together, the C-linker and CBND can be referred to as the “cAMP-sensing domain” (CSD) because they are of functional importance for
5
Page 5 of 120
the cAMP-induced positive shift of the voltage-dependent activation of HCN channels. The crystal structure of CSD has been elucidated at an atomic resolution, but a high-resolution structure of the transmembrane core remains unsolved (Zagotta et al., 2003). HCN channels commonly exist
ip t
in homomeric tetramer configurations in vivo and form four subtypes of homotetramers. The
cr
four subtypes of HCN channels exhibit distinct cAMP-sensitivity with strong HCN2 and HCN4
us
regulation and weak HCN1 and HCN3 regulation. The HCN channel subtypes also have different activation kinetics. The activation of HCN1 is the fastest, while the activation of HCN4 is the
an
slowest. The activation time constants of HCN2 and HCN3 are intermediate. Functional HCN channels also assemble in heteromeric tetramer configurations in heterologous expression
M
systems and normal tissues (Chen et al., 2001b; Much et al., 2003; Ulens and Tytgat, 2001). The assembly of heteromeric complexes increases the diversity of HCN channels, facilitating the
te
d
adaptation of HCN channels to multiple functions in the nervous system. The four subunits display distinct expression patterns in the nervous system (Notomi and
Ac ce p
Shigemoto, 2004), which have been extensively studied at the mRNA and protein levels. HCN1 is primarily expressed in the neocortex, hippocampus, cerebellar cortex and brainstem (Lorincz et al., 2002; Milligan et al., 2006; Moosmang et al., 1999; Santoro et al., 2000; Santoro et al., 1997). HCN2 is prominently distributed throughout almost all brain regions. The highest expression areas are in the thalamus, external of the globus pallidus (GPe) and brainstem nuclei (Chan et al., 2011; Moosmang et al., 1999; Santoro et al., 2000). HCN3 is expressed at low levels in the nervous system. The distributed pattern of HCN4 is complimentary to HCN1, and HCN4 is selectively expressed in various thalamic nuclei and distinct neuronal populations of the basal ganglia and habenular complex (Moosmang et al., 1999; Poller et al., 2011; Santoro et al., 2000).
6
Page 6 of 120
HCN channels have also been identified in peripheral neurons, such as the dorsal root and trigeminal ganglion neurons. All four HCN subunits and Ih have been identified in the dorsal root ganglion, with HCN1 exhibiting the highest expression (Chaplan et al., 2003; Kouranova et al.,
ip t
2008; Mayer and Westbrook, 1983; Moosmang et al., 2001; Scroggs et al., 1994), and the
cr
majority of trigeminal ganglion neurons were immune-positive for HCN1, HCN2 and HCN3 (Wells
us
et al., 2007).
The subcellular localization of HCN channels can be neuron-type-specific. For example, in
an
neocortical and hippocampal pyramidal neurons, HCN channels preferentially target to the distal dendrites to control dendritic excitability and regulate the functional connectivity of the neuronal
M
network (Lorincz et al., 2002). In the interneurons of medial septum, hippocampus and cerebellum, three of the four known HCN channel isoforms (HCN1, 2, and 4) are expressed at
te
d
somatic and axonal regions, where they regulate membrane properties and influence the release of neurotransmitters (Bender and Baram, 2008). The expression of the four HCN subunits might
Ac ce p
be overlapping to assemble heteromeric complexes in some neurons, including hippocampal pyramidal neurons (HCN1 and HCN2), thalamic relay neurons (HCN2 and HCN4), retinal ganglion cells (HCN1 and HCN4) and lateral habenular neurons (HCN2 and HCN4) (Poller et al., 2011; Stradleigh et al., 2011). The different expression patterns, subcelluar localization and coexpression of HCN subunits diversify the biophysical properties of HCN channels and therefore might partially contribute to the different physiological roles of Ih in discrete brain regions.
3. The effects of Ih on membrane properties and associated physiological functions
7
Page 7 of 120
As HCN channels are activated at membrane potentials more negative to -50 mV, a small fraction of HCN channels tonically open at RMP. This inward current exerts two effects on the membrane. First, tonic Ih reduces the membrane input resistance, potentially suppressing
ip t
membrane potential fluctuations to a given current stimulus, dampening dendritic integration
cr
and reducing synaptic-driving neuronal excitability. Second, inward Ih depolarizes the membrane
us
and brings the membrane potential closer to firing threshold. Thus, HCN channel might act as pacemaker channels to initiate rhythmic firing, contribute to subthreshold membrane potential
an
oscillations and influence other ionic conductance. These complex neuronal functions of Ih have been implicated in many physiological activities and are largely dependent on subcellular
M
distribution, channel subtypes, input types and the neurochemical environment (Table 1).
te
d
3.1. Role of Ih in soma and proximal dendrites
Ac ce p
3.1.1. Ih in controlling resting membrane potential The tonic activation of HCN channels actively stabilizes the RMP. In current-clamp experiment,
it has been shown that the in the presence of Ih the voltage response to a given current stimulus was smaller than in the absence of Ih. This effect is attributed to the decrease in membrane input
resistance induced by constitutive Ih (Ludwig et al., 2003; Maccaferri et al., 1993). Furthermore, the dynamic change in voltage-dependent gating of Ih is also involved in its stabilizing effect. When the membrane is hyperpolarized, more HCN channels can be opened. Consequently, a slowly depolarizing inward is generated, which partially counteracts the hyperpolarization and drives the membrane potential back towards the initial value. Conversely, the depolarization of
8
Page 8 of 120
membrane deactivates Ih, which subsequently counteracts depolarization and restores the membrane potential. Therefore, Voltage-dependent activation and deactivation of Ih actively counteract the deviations in the membrane potential away from its initial value. This property is
ip t
due to unusual relation between the activation curve and the reversal potential of Ih. Unlike the
cr
voltage-gated Ca2+ and Na+ channels, the reversal potential of Ih drops close to the base of its
us
activation curve (Lupica et al., 2001; Nolan et al., 2007).
The stabilizing effect of Ih on the RMP is important for normal functions of stellate neurons
an
from layer II of the entorhinal cortex (EC) and of Purkinje cells (PCs) in the cerebellum (Nolan et al., 2007; Nolan et al., 2003). In stellate neurons, HCN1 channels underlie the rapid and full
M
activation of large Ih. The deletion of HCN1 channels from stellate neurons induced large subthreshold fluctuations of the membrane potential in a low frequency band (
S0301-0082(13)00101-9 http://dx.doi.org/doi:10.1016/j.pneurobio.2013.10.001 PRONEU 1300
To appear in:
Progress in Neurobiology
Received date: Revised date: Accepted date:
23-11-2012 1-10-2013 7-10-2013
Please cite this article as: He, Co., Chen, Fg., Li, Bo., Hu, Zn.,Neurophysiology of HCN channels: from cellular functions to multiple regulations, Progress in Neurobiology (2013), http://dx.doi.org/10.1016/j.pneurobio.2013.10.001 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
Neurophysiology of HCN channels: from cellular functions to multiple regulations
ip t
Chao. Hea, Fang. Chena,*, Bo. Lia, b, Zhian. Hua,*
Department of Physiology, Third Military Medical University, Chongqing 400038, PR China
b
Department of Neurosurgery, Jinan General Military Hospital, Jinan, 250031, PR China
us
*
cr
a
Corresponding author at: Department of Physiology, Third Military Medical University,
an
Chongqing 400038, PR China. Tel: +86 23 68752253 (Fang. Chen) or +86 23 68752254 (Zhian. Hu).
M
E-mail address: [email protected] or [email protected]
Abstract
te
d
Hyperpolarization-activated cyclic nucleotide-gated (HCN) cation channels are encoded by HCN1-4 gene family and have four subtypes. These channels are activated upon
Ac ce p
hyperpolarization of membrane potential and conduct an inward, excitatory current Ih in the nervous system. Ih acts as pacemaker current to initiate rhythmic firing, dampen dendritic
excitability and regulate presynaptic neurotransmitter release. This review summarizes recent insights into the cellular functions of Ih and associated behavior such as learning and memory, sleep and arousal. HCN channels are excellent targets of various cellular signals to finely regulate neuronal responses to external stimuli. Numerous mechanisms, including transcriptional control, trafficking, as well as channel assembly and modification, underlie HCN channel regulation. In the next section, we discuss how the intracellular signals, especially recent findings concerning protein kinases and interacting proteins such as cGKII, Ca2+/CaMKII and TRIP8b, regulate function
1
Page 1 of 120
and expression of HCN channels, and subsequently provide an overview of the effects of neurotransmitters on HCN channels and their corresponding intracellular mechanisms. We also
directions in this exciting area of ion channel research is provided.
ip t
discuss the dysregulation of HCN channels in pathological conditions. Finally, insight into future
cr
Key words: Ih, HCN channels, HCN channels trafficking, extracellular molecules, protein kinases,
us
TRIP8b.
an
Contents
M
1. Introduction
2. Structure and distribution of HCN channels
te
d
3. The effects of Ih on membrane properties and associated physiological functions 3.1. Role of Ih in neuronal soma and proximal dendrites
Ac ce p
3.1.1. Ih in controlling resting membrane potential 3.1.2. Ih in neuronal oscillation
3.2. Role of Ih in distal dendrites 3.3. Role of Ih in presynaptic terminals
4. Regulation of HCN channel function 4.1. Regulation of HCN channels by intracellular molecules 4.1.1. Small molecules 4.1.2. Protein kinases 4.1.3. Interacting proteins
2
Page 2 of 120
4.2. Regulation of HCN channels by extracellular neurotransmitters 4.2.1. Acetylcholine 4.2.2. Monoaminergic neurotransmitters
ip t
4.2.3. Glutamate
cr
4.2.4. Purinergic neurotransmitters
4.2.6. Neuropeptides
an
4.3. Regulation of HCN channels during development
us
4.2.5. Nitric oxide
5. Dysregulation of HCN channels is involved in pathological conditions
M
5.1. Epilepsy
te
5.3. Parkinsonian disease
d
5.2. Neuropathic pain
5.4. Age-related working memory decline
Ac ce p
6. Future perspectives References
Acknowledgments
1. Introduction
The hyperpolarization-activated current, Ih, was first observed in sino-atrial node tissue in 1976 and later was identified in rod photoreceptors and hippocampal pyramidal neurons (Bader et al., 1979; Halliwell and Adams, 1982; Noma and Irisawa, 1976). Due to its unique properties,
3
Page 3 of 120
particularly the activation upon hyperpolarization of the membrane potential, Ih has been also termed If (f for funny) or Iq (q for queer). The hyperpolarization-activated cyclic nucleotide-gated (HCN) cation ion channels underlying Ih were discovered in the late 1990s and subsequently, the
ip t
genes encoding these channels were identified, which enable the expression of HCN channels in
cr
heterologous systems (Ludwig et al., 1998; Ludwig et al., 1999; Santoro et al., 1998; Seifert et al.,
us
1999).
Unlike most other voltage-gated channels, the activation of HCN channels is controlled through
an
dually interdependent membrane potentials and cAMP binding (Kusch et al., 2010; Wu et al., 2011). HCN channels are activated upon hyperpolarization of the membrane potential with
M
sigmoidal kinetics, and this process is facilitated through cAMP, which directly interacts with the channel proteins. These channels do not exhibit voltage-dependent inactivation, and opening
te
d
HCN channel allows the permeability of K + and Na+ ions for the generation of the inward current Ih in the nervous system (Biel et al., 2009; Wahl-Schott and Biel, 2009). Ih contributes to diverse
Ac ce p
neuronal functions, including the determination of resting membrane potential (RMP), generation of neuronal oscillation, and regulation of dendritic integration and synaptic transmission, and is implicated in multiple physiological processes, such as sleep and arousal, learning and memory, and sensation and perception. In the nervous system, the functional properties and expression of HCN channels are diversified to adapt to the corresponding physiological roles, due to the dynamic and precise regulation of these channels through a wide range of cellular signals. The regulation of HCN channels involves short-term regulation through cellular metabolites that directly interact with these channels or protein kinases that induce phosphorylation of channel proteins, and long-term regulation via the regulation of channel
4
Page 4 of 120
expression, heteromerization or subcellular redistribution. In this review, we provide a brief up-to-date summary of the biophysical properties, structure and distribution patterns of HCN channels in the nervous system. These aspects of HCN channels
ip t
have been well reviewed, and more detailed information can be obtained from several excellent
cr
prior publications (Wahl-Schott and Biel, 2009; Robinson and Siegelbaum, 2003; Postea and Biel,
us
2011). Accordingly, we focus on the recent insights into the effects of Ih on membrane properties, the associated physiological functions, and regulation mechanisms underlying HCN channels.
an
Finally, we provide an overview of the dysfunction of HCN channels and corresponding cellular mechanisms in pathological conditions with the goal of identifying the role of dysregulated HCN
M
channels in the pathogenesis of several diseases.
te
d
2. Structure and distribution of HCN channels
Ac ce p
HCN channels belong to the superfamily of voltage-gated pore loop channels with four
pore-forming subunits (HCN1-4) encoded by the HCN1-4 gene family in mammals (Robinson and Siegelbaum, 2003). Each subunit has six transmembrane helices (S1-S6), with the positively charged voltage sensor (S4) and the pore region carrying the GYG motif between S5 and S6, which forms the ion selectivity filter (Macri et al., 2012). Following S6 is the 80-residue C-linker comprising six -helices (A’-F’) and the cyclic nucleotide-binding domain (CNBD). The CNBD consists of three -helices (A-C) and a β-roll between the A- and B-helices (Fig. 1) (Biel et al., 2009; Wahl-Schott and Biel, 2009; Wicks et al., 2011). Together, the C-linker and CBND can be referred to as the “cAMP-sensing domain” (CSD) because they are of functional importance for
5
Page 5 of 120
the cAMP-induced positive shift of the voltage-dependent activation of HCN channels. The crystal structure of CSD has been elucidated at an atomic resolution, but a high-resolution structure of the transmembrane core remains unsolved (Zagotta et al., 2003). HCN channels commonly exist
ip t
in homomeric tetramer configurations in vivo and form four subtypes of homotetramers. The
cr
four subtypes of HCN channels exhibit distinct cAMP-sensitivity with strong HCN2 and HCN4
us
regulation and weak HCN1 and HCN3 regulation. The HCN channel subtypes also have different activation kinetics. The activation of HCN1 is the fastest, while the activation of HCN4 is the
an
slowest. The activation time constants of HCN2 and HCN3 are intermediate. Functional HCN channels also assemble in heteromeric tetramer configurations in heterologous expression
M
systems and normal tissues (Chen et al., 2001b; Much et al., 2003; Ulens and Tytgat, 2001). The assembly of heteromeric complexes increases the diversity of HCN channels, facilitating the
te
d
adaptation of HCN channels to multiple functions in the nervous system. The four subunits display distinct expression patterns in the nervous system (Notomi and
Ac ce p
Shigemoto, 2004), which have been extensively studied at the mRNA and protein levels. HCN1 is primarily expressed in the neocortex, hippocampus, cerebellar cortex and brainstem (Lorincz et al., 2002; Milligan et al., 2006; Moosmang et al., 1999; Santoro et al., 2000; Santoro et al., 1997). HCN2 is prominently distributed throughout almost all brain regions. The highest expression areas are in the thalamus, external of the globus pallidus (GPe) and brainstem nuclei (Chan et al., 2011; Moosmang et al., 1999; Santoro et al., 2000). HCN3 is expressed at low levels in the nervous system. The distributed pattern of HCN4 is complimentary to HCN1, and HCN4 is selectively expressed in various thalamic nuclei and distinct neuronal populations of the basal ganglia and habenular complex (Moosmang et al., 1999; Poller et al., 2011; Santoro et al., 2000).
6
Page 6 of 120
HCN channels have also been identified in peripheral neurons, such as the dorsal root and trigeminal ganglion neurons. All four HCN subunits and Ih have been identified in the dorsal root ganglion, with HCN1 exhibiting the highest expression (Chaplan et al., 2003; Kouranova et al.,
ip t
2008; Mayer and Westbrook, 1983; Moosmang et al., 2001; Scroggs et al., 1994), and the
cr
majority of trigeminal ganglion neurons were immune-positive for HCN1, HCN2 and HCN3 (Wells
us
et al., 2007).
The subcellular localization of HCN channels can be neuron-type-specific. For example, in
an
neocortical and hippocampal pyramidal neurons, HCN channels preferentially target to the distal dendrites to control dendritic excitability and regulate the functional connectivity of the neuronal
M
network (Lorincz et al., 2002). In the interneurons of medial septum, hippocampus and cerebellum, three of the four known HCN channel isoforms (HCN1, 2, and 4) are expressed at
te
d
somatic and axonal regions, where they regulate membrane properties and influence the release of neurotransmitters (Bender and Baram, 2008). The expression of the four HCN subunits might
Ac ce p
be overlapping to assemble heteromeric complexes in some neurons, including hippocampal pyramidal neurons (HCN1 and HCN2), thalamic relay neurons (HCN2 and HCN4), retinal ganglion cells (HCN1 and HCN4) and lateral habenular neurons (HCN2 and HCN4) (Poller et al., 2011; Stradleigh et al., 2011). The different expression patterns, subcelluar localization and coexpression of HCN subunits diversify the biophysical properties of HCN channels and therefore might partially contribute to the different physiological roles of Ih in discrete brain regions.
3. The effects of Ih on membrane properties and associated physiological functions
7
Page 7 of 120
As HCN channels are activated at membrane potentials more negative to -50 mV, a small fraction of HCN channels tonically open at RMP. This inward current exerts two effects on the membrane. First, tonic Ih reduces the membrane input resistance, potentially suppressing
ip t
membrane potential fluctuations to a given current stimulus, dampening dendritic integration
cr
and reducing synaptic-driving neuronal excitability. Second, inward Ih depolarizes the membrane
us
and brings the membrane potential closer to firing threshold. Thus, HCN channel might act as pacemaker channels to initiate rhythmic firing, contribute to subthreshold membrane potential
an
oscillations and influence other ionic conductance. These complex neuronal functions of Ih have been implicated in many physiological activities and are largely dependent on subcellular
M
distribution, channel subtypes, input types and the neurochemical environment (Table 1).
te
d
3.1. Role of Ih in soma and proximal dendrites
Ac ce p
3.1.1. Ih in controlling resting membrane potential The tonic activation of HCN channels actively stabilizes the RMP. In current-clamp experiment,
it has been shown that the in the presence of Ih the voltage response to a given current stimulus was smaller than in the absence of Ih. This effect is attributed to the decrease in membrane input
resistance induced by constitutive Ih (Ludwig et al., 2003; Maccaferri et al., 1993). Furthermore, the dynamic change in voltage-dependent gating of Ih is also involved in its stabilizing effect. When the membrane is hyperpolarized, more HCN channels can be opened. Consequently, a slowly depolarizing inward is generated, which partially counteracts the hyperpolarization and drives the membrane potential back towards the initial value. Conversely, the depolarization of
8
Page 8 of 120
membrane deactivates Ih, which subsequently counteracts depolarization and restores the membrane potential. Therefore, Voltage-dependent activation and deactivation of Ih actively counteract the deviations in the membrane potential away from its initial value. This property is
ip t
due to unusual relation between the activation curve and the reversal potential of Ih. Unlike the
cr
voltage-gated Ca2+ and Na+ channels, the reversal potential of Ih drops close to the base of its
us
activation curve (Lupica et al., 2001; Nolan et al., 2007).
The stabilizing effect of Ih on the RMP is important for normal functions of stellate neurons
an
from layer II of the entorhinal cortex (EC) and of Purkinje cells (PCs) in the cerebellum (Nolan et al., 2007; Nolan et al., 2003). In stellate neurons, HCN1 channels underlie the rapid and full
M
activation of large Ih. The deletion of HCN1 channels from stellate neurons induced large subthreshold fluctuations of the membrane potential in a low frequency band (
