Neurophysiology of HCN channels: From cellular functions to multiple regulations

He, Chaochao; Chen, Fang‐Fang; Li, Bo; Hu, Zhian

doi:10.1016/j.pneurobio.2013.10.001

Cited by 298 publications

(326 citation statements)

References 250 publications

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“…However, the Aplysia channels appear to have two differences compared with mammals (4,6,8,31). First, in Aplysia the gating of the acHCN channels by cyclic nucleotides was associated primarily with an increase in I h amplitude rather than in a voltage-dependence shift (e.g., a positive shift of 2.2 mV in the presence of 1 mM 8-Br-cAMP and 1.5 mV in the presence of 8-Br-cGMP; n = 4 in each test).…”

Section: Hcn Channels Expressed In Xenopus Oocytes Share Overall Simimentioning

confidence: 99%

“…In addition, binding of cyclic nucleotides (cAMP and cGMP) to the C-terminal cyclic nucleotide binding domain (CNBD) enhances I h and thus couples membrane excitability with intracellular signaling pathways (2, 4). HCN channels are widely important for numerous systemic functions such as hormonal regulation, heart contractility, epilepsy, pain, central pattern generation, sensory perception (4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15), and learning and memory (16)(17)(18)(19)(20)(21)(22)(23)(24).…”

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confidence: 99%

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Hyperpolarization-activated, cyclic nucleotide-gated cation channels in Aplysia : Contribution to classical conditioning

Yang

Kuzyk

Antonov

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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Hyperpolarization-activated, cyclic nucleotide-gated cation (HCN) channels are critical regulators of neuronal excitability, but less is known about their possible roles in synaptic plasticity and memory circuits. Here, we characterized the HCN gene organization, channel properties, distribution, and involvement in associative and nonassociative forms of learning in Aplysia californica. Aplysia has only one HCN gene, which codes for a channel that has many similarities to the mammalian HCN channel. The cloned acHCN gene was expressed in Xenopus oocytes, which displayed a hyperpolarization-induced inward current that was enhanced by cGMP as well as cAMP. Similarly to its homologs in other animals, acHCN is permeable to K + and Na + ions, and is selectively blocked by Cs + and ZD7288. We found that acHCN is predominantly expressed in inter-and motor neurons, including LFS siphon motor neurons, and therefore tested whether HCN channels are involved in simple forms of learning of the siphon-withdrawal reflex in a semiintact preparation. ZD7288 (100 μM) significantly reduced an associative form of learning (classical conditioning) but had no effect on two nonassociative forms of learning (intermediate-term sensitization and unpaired training) or baseline responses. The HCN current is enhanced by nitric oxide (NO), which may explain the postsynaptic role of NO during conditioning. HCN current in turn enhances the NMDA-like current in the motor neurons, suggesting that HCN channels contribute to conditioning through this pathway.HCN channels | learning and memory | NMDA | nitric oxide | Aplysia H yperpolarization-activated, cyclic nucleotide-gated (HCN), cation nonselective ion channels generate hyperpolarization-activated inward currents (I h ) and thus tend to stabilize membrane potential (1-3). In addition, binding of cyclic nucleotides (cAMP and cGMP) to the C-terminal cyclic nucleotide binding domain (CNBD) enhances I h and thus couples membrane excitability with intracellular signaling pathways (2, 4). HCN channels are widely important for numerous systemic functions such as hormonal regulation, heart contractility, epilepsy, pain, central pattern generation, sensory perception (4-15), and learning and memory (16-24).However, in previous studies it has been difficult to relate the cellular effects of HCN channels directly to their behavioral effects, because of the immense complexity of the mammalian brain. We have therefore investigated the role of HCN channels in Aplysia, which has a numerically simpler nervous system (25). We first identified and characterized an HCN gene in Aplysia, and showed that it codes for a channel that has many similarities to the mammalian HCN channel. We found that the Aplysia HCN channel is predominantly expressed in motor neurons including LFS neurons in the siphon withdrawal reflex circuit (26, 27). We therefore investigated simple forms of learning of that reflex in a semiintact preparation (28-30) and found that HCN current is involved in classical conditioning and enhances the ...

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Section: Hcn Channels Expressed In Xenopus Oocytes Share Overall Simimentioning

confidence: 99%

mentioning

confidence: 99%

Hyperpolarization-activated, cyclic nucleotide-gated cation channels in Aplysia : Contribution to classical conditioning

Yang

Kuzyk

Antonov

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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“…cAMP, PIP2, protons) and protein kinases (e.g. Src, p38-MAPK, PKC, cGKII, Ca2+/CaMKII), that influence HCN channel gating, kinetics and surface expression [37,54,55]. In fact, selective serotonin reuptake inhibitor (SSRI) antidepressants, whose primary action is based on the inhibition of 5-HT reuptake in the central nervous system, have been used with FDA approved drugs for dementia in AD.…”

Section: Reviewmentioning

confidence: 99%

“…Providing the large overlap between AD and VaD in clinical symptomatology, pathophysiology and neurochemical mechanisms [60][61][62][63], an effective treatment for AD may also offer benefits as a symptomatic treatment in VaD. Although most of the effects of antidepressants have been ascribed to their functions of neurogenesis activity, neurotrophin modulation and reduction of proteotoxicity [64][65][66][67], it is possible that acting on HCN channels may also contribute to or be responsible for antidepressants' efficacy on dementia since there is an interaction between the serotonergic systems and HCN channels [68][69][70] and SSRI antidepressants inhibit 5-HT reuptake that can regulate the properties and trafficking of HCN channels via a way of activating PLC-PKA and p38-MAPK signaling pathways (Figure 2) [54,[71][72][73]. It is worth mentioning that we have recently observed that fluoxetine can ameliorate cognitive impairments induced by CCH via down-regulation of HCN2 surface expression in the hippocampal CA1 area in rats (The data have not been published) and data from others also have showed that SB202190, a p38-MAPK inhibitor, can significantly reduce neuronal apoptosis in the hippocampus and rescue spatial learning and memory deficits in a rat model of vascular dementia [74].…”

Section: Reviewmentioning

confidence: 99%

“…In additional, acetylcholinesterase inhibitors such as galantamine have a long-term safety and cognitive effects in the treatment of probable VaD or AD with cerebrovascular disease [75][76][77][78]. Because acetylcholine generally exerts an inhibitory effect on Ih via a cAMP signaling way [54], galantamine may have a high propensity to modulate HCN channels, which may also participate in the mechanisms of its efficacy. What's more, CaMKII increases channels surface expression through the interacting protein TRIP8b (1a-4) or reduces the HCN gene transcription via Neuronal Restrictive Silencing Factor (NRSF) in pathological conditions [54], this target may also provide interventions for the treatment of VaD.…”

Section: Reviewmentioning

confidence: 99%

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HCN Channels: From the Role in Chronic Cerebral Hypoperfusion-Induced Cognitive Impairments to a New Therapeutic Target for Vascular Dementia

Luo¹,

Guo

2015

J Neurol Neurophysiol

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Hyperpolarization-activated cyclic nucleotide-gated channels are concentrated in cortical and hippocampal pyramidal cell dendrites, where they play an important role in determining synaptic integration and plasticity phenomena. These channels have been suggested to be involved in physiological processes such as cognition as well as pathophysiological states such as epilepsy, pain, Parkinson's disease (PD) and Alzheimer's disease (AD). Recent evidences from our own researches have suggested that the learning and memory impairments caused by chronic cerebral hypoperfusion (CCH) are associated with a change of HCN1/HCN2 expression; therefore these channels may also be therapeutic targets for treatment of vascular dementia. Keywords: Vascular dementia; HCN channels; Chronic cerebral hypoperfusion ReviewVascular dementia (VaD) is the second leading form of dementia after Alzheimer's disease (AD) among western countries [1]. It is a progressive disease caused by cerebrovascular diseases with the pathologic features of reduced blood flow in the brain that affects cognitive abilities [2][3][4]. Accordingly, the cognitive impairment associated with vessel disorders is an increasingly important and recognised area of the medicine of VaD patients. CCH is a common consequence of various cerebral vascular disorders and hemodynamic changes that contributes to the risk of VaD. In rodents, the bilateral common carotid artery occlusion (2VO) model is so far the most effective and frequently-used experimental model to evaluate the relation between chronic cerebral hypoperfusion and vascular diseaserelated dementia [2,[5][6][7]. However, the progress on understanding the basis of the disease and developing treatments is not encouraging. There are no drugs licensed for the treatment of VaD. In this context, we reviewed the discoveries from our own research based on 2VO model that the role of HCN channels in CCH-induced cognitive impairments and hypothesise a new therapeutic target toward developing novel treatments for dementia of vascular origin.HCN channels are cation channels that open at membrane voltages close to resting membrane potentials and are directly regulated by the binding of cAMP. It was identified in the late 1970s in sinoatrial node cells and neurons [8][9][10][11]. The HCN channel family is comprised of four subtypes (HCN1-4). The predominant forms in the hippocampus and cortex are HCN1 and HCN2 [12,13]. In pyramidal and neocortical neurons, they show a large gradient of expression that can be 60-fold increase from somatic to distal apical dendritic membranes [14]. The channels are formed by heteromeric or homomeric complexes and carry the hyperpolarization-activated current, Ih. In neuronal dendrites, Ih is proposed to be responsible for several important cellular functions and plays a fundamental role in controlling cellular excitability, rhythmic activity, dendritic integration, synaptic transmission, and plasticity phenomena [15][16][17] that participates in the pathogenic mechanism of certain neurolog...

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Association of Pituitary Adenylate Cyclase–Activating Polypeptide With Cognitive Decline in Mild Cognitive Impairment Due to Alzheimer Disease

et al. 2015

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IMPORTANCE There is a deficit of pituitary adenylate cyclase-activating polypeptide (PACAP) in patients with neuropathologically confirmed Alzheimer dementia. However, whether this deficit is associated with the earlier stages of Alzheimer disease (AD) is unknown. This study was conducted to clarify the association between PACAP biomarkers and preclinical, mild cognitive impairment (MCI), and dementia stages of AD in postmortem brain tissue.OBJECTIVES To examine PACAP and PACAP receptor levels in postmortem brain tissues and cerebrospinal fluid from cognitively and neuropathologically normal control individuals, patients with MCI due to AD (MCI-AD), and individuals with AD; analyze the relationship between PACAP, cognitive, and pathologic features; and propose a model to assess these relationships. DESIGN, SETTING, AND PARTICIPANTSWe measured PACAP and its receptor (PAC1) levels using enzyme-linked immunoassay. A total of 35 cases were included. All the brain tissue and cerebrospinal fluid samples were selected from Banner Sun Health Research Institute Brain and Body Donation Program. All cognitive test results were in record with the Arizona Alzheimer's Consortium. MAIN OUTCOMES AND MEASURESA comparison of PACAP and PAC1 levels among the healthy controls, MCI-AD, and AD dementia groups, as well as a systematic correlation analysis between PACAP level, cognitive performance, and pathologic severity. RESULTSThe PACAP levels in cerebrospinal fluid, the superior frontal gyrus, and the middle temporal gyrus were inversely related to dementia severity. The PACAP levels in cerebrospinal fluid correlated with the Mattis Dementia Rating Scale score (Pearson r = 0.50; P = .03) and inversely correlated with total amyloid plaques (Pearson r = −0.48; P < .01) and tangles (Pearson r = −0.55; P = .01) in the brain. The PACAP in the superior frontal gyrus and middle temporal gyrus correlated with the Stroop Color-Word Interference Test (Pearson r = 0.58; P < .01) and the Auditory Verbal Learning Test-Total Learning (Pearson r = 0.33; P = .02), respectively. The PACAP in the primary visual cortex did not correlate with the Judgment of Line orientation test (P = .14). Furthermore, the PAC1 level in the superior frontal gyrus showed an upregulation in MCI-AD but not in AD. The pharmacodynamic model of the PACAP-PAC1 interaction best predicted cognitive function in the superior frontal gyrus, but it was less predictive in the middle temporal gyrus and failed to be predictive in the primary visual cortex.CONCLUSIONS AND RELEVANCE Deficits in PACAP are associated with clinical severity in the MCI and dementia stages of AD. Additional studies are needed to clarify the role of PACAP deficits in the predisposition to, pathogenesis of, and treatment of AD.

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Neurophysiology of HCN channels: From cellular functions to multiple regulations

Cited by 298 publications

References 250 publications

Hyperpolarization-activated, cyclic nucleotide-gated cation channels in Aplysia : Contribution to classical conditioning

Hyperpolarization-activated, cyclic nucleotide-gated cation channels in Aplysia : Contribution to classical conditioning

HCN Channels: From the Role in Chronic Cerebral Hypoperfusion-Induced Cognitive Impairments to a New Therapeutic Target for Vascular Dementia

Association of Pituitary Adenylate Cyclase–Activating Polypeptide With Cognitive Decline in Mild Cognitive Impairment Due to Alzheimer Disease

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