Faculty Opinions recommendation of HCN channels segregate stimulation-evoked movement responses in neocortex and allow for coordinated forelimb movements in rodents.

Chronic Heart Failure (CHF) is a complex clinical syndrome with a high incidence worldwide. Although various types of pharmacological and device therapies are available for CHF, the prognosis is not ideal, for which, the control of increased Heart Rate (HR) is critical. Recently, a bradycardic agent, ivabradine, is found to reduce HR by inhibiting the funny current (If). The underlying mechanism states that ivabradine can enter the Hyperpolarization-activated Cyclic Nucleotide-gated (HCN) channels and bind to the intracellular side, subsequently inhibiting the If. This phenomenon can prolong the slow spontaneous phase in the diastolic depolarization, and thus, reduce HR. The clinical trials demonstrated the significant effects of the drug on reducing HR and improving the symptoms of CHF with fewer adverse effects. This review primarily introduces the chemical features and pharmacological characteristics of ivabradine and the mechanism of treating CHF. Also, some expected therapeutic effects on different diseases were also concluded. However, ivabradine, as a typical If channel inhibitor, necessitates additional research to verify its pharmacological functions.

Download Full-text

AAV-Mediated CRISPRi and RNAi Based Gene Silencing in Mouse Hippocampal Neurons

Cells ◽

10.3390/cells10020324 ◽

2021 ◽

Vol 10 (2) ◽

pp. 324

Author(s):

Matthias Deutsch ◽

Anne Günther ◽

Rodrigo Lerchundi ◽

Christine R. Rose ◽

Sabine Balfanz ◽

...

Keyword(s):

Gene Expression ◽

Transcription Initiation ◽

Hippocampal Neurons ◽

De Novo ◽

Protein Biosynthesis ◽

Physiological Role ◽

High Specificity ◽

Hcn Channels ◽

Proliferating Cells ◽

Neuronal Tissues

Uncovering the physiological role of individual proteins that are part of the intricate process of cellular signaling is often a complex and challenging task. A straightforward strategy of studying a protein’s function is by manipulating the expression rate of its gene. In recent years, the Clustered Regularly Interspaced Short Palindromic Repeat (CRISPR)/Cas9-based technology was established as a powerful gene-editing tool for generating sequence specific changes in proliferating cells. However, obtaining homogeneous populations of transgenic post-mitotic neurons by CRISPR/Cas9 turned out to be challenging. These constraints can be partially overcome by CRISPR interference (CRISPRi), which mediates the inhibition of gene expression by competing with the transcription machinery for promoter binding and, thus, transcription initiation. Notably, CRISPR/Cas is only one of several described approaches for the manipulation of gene expression. Here, we targeted neurons with recombinant Adeno-associated viruses to induce either CRISPRi or RNA interference (RNAi), a well-established method for impairing de novo protein biosynthesis by using cellular regulatory mechanisms that induce the degradation of pre-existing mRNA. We specifically targeted hyperpolarization-activated and cyclic nucleotide-gated (HCN) channels, which are widely expressed in neuronal tissues and play essential physiological roles in maintaining biophysical characteristics in neurons. Both of the strategies reduced the expression levels of three HCN isoforms (HCN1, 2, and 4) with high specificity. Furthermore, detailed analysis revealed that the knock-down of just a single HCN isoform (HCN4) in hippocampal neurons did not affect basic electrical parameters of transduced neurons, whereas substantial changes emerged in HCN-current specific properties.

Download Full-text

Distribution and Function of HCN Channels in the Apical Dendritic Tuft of Neocortical Pyramidal Neurons

Journal of Neuroscience ◽

10.1523/jneurosci.2813-14.2015 ◽

2015 ◽

Vol 35 (3) ◽

pp. 1024-1037 ◽

Cited By ~ 60

Author(s):

M. T. Harnett ◽

J. C. Magee ◽

S. R. Williams

Keyword(s):

Pyramidal Neurons ◽

Hcn Channels ◽

And Function ◽

Neocortical Pyramidal Neurons

Download Full-text

cAMP-PKA signaling is involved in regulation of spinal HCN channels function in diabetic neuropathic pain

Neuroscience Letters ◽

10.1016/j.neulet.2021.135763 ◽

2021 ◽

Vol 750 ◽

pp. 135763

Author(s):

Yanqiao Ma ◽

Ji Chen ◽

Deqian Yu ◽

Bangcong Wei ◽

Huan Jin ◽

...

Keyword(s):

Neuropathic Pain ◽

Hcn Channels ◽

Diabetic Neuropathic Pain

Download Full-text

Genetic Analysis of Hyperpolarisation-Activated Cyclic Nucleotide-Gated Cation (HCN) Channels in Sudden Unexpected Death in Epilepsy (SUDEP) Cases

Heart Lung and Circulation ◽

10.1016/j.hlc.2011.05.539 ◽

2011 ◽

Vol 20 ◽

pp. S219

Author(s):

E. Tu ◽

L. Waterhouse ◽

J. Duflou ◽

R. Bagnall ◽

C. Semsarian

Keyword(s):

Genetic Analysis ◽

Cyclic Nucleotide ◽

Sudden Unexpected Death ◽

Hcn Channels ◽

Unexpected Death

Download Full-text

The Role of HCN Channels on Membrane Excitability in the Nervous System

Journal of Signal Transduction ◽

10.1155/2012/619747 ◽

2012 ◽

Vol 2012 ◽

pp. 1-11 ◽

Cited By ~ 38

Author(s):

Daisuke Kase ◽

Keiji Imoto

Keyword(s):

Intracellular Signaling ◽

Hcn Channels ◽

Heart Cells ◽

Hcn Channel ◽

Membrane Excitability ◽

Wide Range ◽

Inward Currents ◽

Range Of Functions ◽

Channel Currents

Hyperpolarization-activated and cyclic nucleotide-gated (HCN) channels were first reported in heart cells and are recently known to be involved in a variety of neural functions in healthy and diseased brains. HCN channels generate inward currents when the membrane potential is hyperpolarized. Voltage dependence of HCN channels is regulated by intracellular signaling cascades, which contain cyclic AMP, PIP2, and TRIP8b. In addition, voltage-gated potassium channels have a strong influence on HCN channel activity. Because of these funny features, HCN channel currents, previously called funny currents, can have a wide range of functions that are determined by a delicate balance of modulatory factors. These multifaceted features also make it difficult to predict and elucidate the functional role of HCN channels in actual neurons. In this paper, we focus on the impacts of HCN channels on neural activity. The functions of HCN channels reported previously will be summarized, and their mechanisms will be explained by using numerical simulation of simplified model neurons.

Download Full-text