The fast and slow ups and downs of HCN channel regulation

Lewis, Alan S.; Estep, Chad M; Chetkovich, Dane M.

doi:10.4161/chan.4.3.11630

Cited by 42 publications

(36 citation statements)

References 150 publications

(261 reference statements)

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“…That pre-synaptic HCN channel properties are unchanged in TRIP8b null neurons suggests that the molecular composition and biophysical properties of pre-synaptic HCN channels differs from those present post-synaptically. Post-synaptic HCN channels, though, are subject to phosphorylation and their properties can be affected by alterations in intracellular calcium concentrations (Biel et al, 2009; Lewis et al, 2010). It remains to be determined if pre-synaptic HCN channels are also modulated by other intracellular signalling molecules.…”

Section: Discussionmentioning

confidence: 99%

TRIP8b-Independent Trafficking and Plasticity of Adult Cortical Presynaptic HCN1 Channels

et al. 2012

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Hyperpolarization-activated cyclic nucleotide-gated (HCN) channels are subthreshold activated voltage-gated ion channels. In the cortex, these channels are predominantly expressed in dendrites where they significantly modify dendritic intrinsic excitability as well synaptic potential shapes and integration. HCN channel trafficking to dendrites is regulated by the protein, TRIP8b. Additionally, altered TRIP8b expression may be one mechanism underlying seizure-induced dendritic HCN channel plasticity. HCN channels, though, are also located in certain mature cortical synaptic terminals, where they play a vital role in modulating synaptic transmission. In this study, using electrophysiological recordings as well as electron microscopy we show that pre-synaptic, but not dendritic, cortical HCN channel expression and function is comparable in adult TRIP8b null mice and wildtype littermates. We further investigated if pre-synaptic HCN channels undergo seizure-dependent plasticity. We found that, like dendritic channels, wildtype pre-synaptic HCN channel function was persistently decreased following induction of kainic acid-induced seizures. Since TRIP8b does not affect pre-synaptic HCN subunit trafficking, seizure dependent plasticity of these cortical HCN channels is not conditional upon TRIP8b. Our results, thus, suggest that the molecular mechanisms underlying HCN subunit targeting, expression and plasticity in adult neurons is compartment selective, providing a means by which pre- and post-synaptic processes that are critically dependent upon HCN channel function may be distinctly influenced.

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Section: Discussionmentioning

confidence: 99%

TRIP8b-Independent Trafficking and Plasticity of Adult Cortical Presynaptic HCN1 Channels

et al. 2012

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“…There is growing evidence that the poreforming HCN channel core is associated in vivo with a variety of accessory proteins that regulate the biophysical properties of the channel, control cellular targeting, and/or functionally link the channel to cellular signaling pathways (13). The most extensively characterized member of the HCN channel accessory proteins is TRIP8b, which was identified in a yeast two-hybrid screen using the HCN1 C terminus as bait (14), and was later on also found in a proteomics approach for the other three HCN isoforms (15).…”

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confidence: 99%

Up-regulation of Hyperpolarization-activated Cyclic Nucleotide-gated Channel 3 (HCN3) by Specific Interaction with K+ Channel Tetramerization Domain-containing Protein 3 (KCTD3)

Cao-Ehlker

Zong²,

Hammelmann³

et al. 2013

Journal of Biological Chemistry

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Background: HCN channels are key regulators of neuronal excitability. Results: We identify KCTD3 as a protein that specifically interacts with HCN3 in brain and up-regulates cell surface expression of this channel. Conclusion: KCTD3 is a novel accessory subunit of neuronal HCN3 channels. Significance: The identification of KCTD3 is an important step toward achieving a better understanding of the in vivo role of HCN3.

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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%

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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The fast and slow ups and downs of HCN channel regulation

Cited by 42 publications

References 150 publications

TRIP8b-Independent Trafficking and Plasticity of Adult Cortical Presynaptic HCN1 Channels

TRIP8b-Independent Trafficking and Plasticity of Adult Cortical Presynaptic HCN1 Channels

Up-regulation of Hyperpolarization-activated Cyclic Nucleotide-gated Channel 3 (HCN3) by Specific Interaction with K+ Channel Tetramerization Domain-containing Protein 3 (KCTD3)

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

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