Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels

2019 ◽  
Author(s):  
Alessio Masi ◽  
Maria Novella Romanelli ◽  
Guido Mannaioni ◽  
Elisabetta Cerbai
Keyword(s):  
Cyclic Nucleotide ◽  
Hcn Channels ◽  
Neuronal Function ◽  
Excitable Cells ◽  
Cyclic Nucleotide Gated Channels ◽  
Pathological Conditions ◽  
Heart Muscle Cells ◽  
Neuronal Types ◽  
Close Relatives ◽  
Critical Aspects

Hyperpolarization-activated, cyclic nucleotide-gated (HCN) channels are members of the voltage-gated K+ channels family, but with unique properties. In stark contrast to close relatives, HCN channels are permeable to both Na+ and K+, and they are activated by hyperpolarization. Activation by hyperpolarization is indeed a pretty funny feature, to the point that the physiologists who first characterized HCN current in heart muscle cells named it “funny current” or I f. Since then, the funny current has also been recorded from several neuronal types in both the central and peripheral nervous systems, as well as from some non-excitable cells, becoming progressively less “funny” over the years. In fact, HCN current goes now by the more serious designation of “I h,” for “hyperpolarization-activated.” Forty years after the first current recording, it is now established that HCN channels, by virtue of their special properties and a host of modulatory mechanisms, are profoundly involved in many critical aspects of neuronal function in physiological and pathological conditions.

scholarly journals Hyperpolarization-activated cyclic-nucleotide-gated channels potentially modulate axonal excitability at different thresholds

2017 ◽  
Vol 118 (6) ◽  
pp. 3044-3050 ◽  
Author(s):  
Dinushi Weerasinghe ◽  
Parvathi Menon ◽  
Steve Vucic
Keyword(s):  
Cyclic Nucleotide ◽  
Neurological Diseases ◽  
Lower Threshold ◽  
Resting Membrane Potential ◽  
Hcn Channels ◽  
Motor Axons ◽  
Cyclic Nucleotide Gated Channels ◽  
Sensory Axons ◽  
Current Threshold ◽  
Axonal Excitability

Hyperpolarization-activated cyclic-nucleotide-gated (HCN) channels mediate differences in sensory and motor axonal excitability at different thresholds in animal models. Importantly, HCN channels are responsible for voltage-gated inward rectifying ( Ih) currents activated during hyperpolarization. The Ih currents exert a crucial role in determining the resting membrane potential and have been implicated in a variety of neurological disorders, including neuropathic pain. In humans, differences in biophysical properties of motor and sensory axons at different thresholds remain to be elucidated and could provide crucial pathophysiological insights in peripheral neurological diseases. Consequently, the aim of this study was to characterize sensory and motor axonal function at different threshold. Median nerve motor and sensory axonal excitability studies were undertaken in 15 healthy subjects (45 studies in total). Tracking targets were set to 20, 40, and 60% of maximum for sensory and motor axons. Hyperpolarizing threshold electrotonus (TEh) at 90–100 ms was significantly increased in lower threshold sensory axons times ( F = 11.195, P < 0.001). In motor axons, the hyperpolarizing current/threshold ( I/ V) gradient was significantly increased in lower threshold axons ( F = 3.191, P < 0.05). The minimum I/ V gradient was increased in lower threshold motor and sensory axons. In conclusion, variation in the kinetics of HCN isoforms could account for the findings in motor and sensory axons. Importantly, assessing the function of HCN channels in sensory and motor axons of different thresholds may provide insights into the pathophysiological processes underlying peripheral neurological diseases in humans, particularly focusing on the role of HCN channels with the potential of identifying novel treatment targets. NEW & NOTEWORTHY Hyperpolarization-activated cyclic-nucleotide-gated (HCN) channels, which underlie inward rectifying currents ( Ih), appear to mediate differences in sensory and motor axonal properties. Inward rectifying currents are increased in lower threshold motor and sensory axons, although different HCN channel isoforms appear to underlie these changes. While faster activating HCN channels seem to underlie Ih changes in sensory axons, slower activating HCN isoforms appear to be mediating the differences in Ih conductances in motor axons of different thresholds. The differences in HCN gating properties could explain the predilection for dysfunction of sensory and motor axons in specific neurological diseases.

scholarly journals Hyperpolarization-activated cyclic nucleotide-gated channels in peripheral diaphragmatic lymphatics

2016 ◽  
Vol 311 (4) ◽  
pp. H892-H903 ◽  
Author(s):  
Daniela Negrini ◽  
Cristiana Marcozzi ◽  
Eleonora Solari ◽  
Elena Bossi ◽  
Raffaella Cinquetti ◽  
...  
Keyword(s):  
Cyclic Nucleotide ◽  
Cesium Chloride ◽  
Spontaneous Contraction ◽  
Hcn Channels ◽  
Contraction Frequency ◽  
Cyclic Nucleotide Gated Channels ◽  
Perfusion Chamber ◽  
Molecular Machinery ◽  
Pressure Changes ◽  
Zd 7288

Diaphragmatic lymphatic function is mainly sustained by pressure changes in the tissue and serosal cavities during cardiorespiratory cycles. The most peripheral diaphragmatic lymphatics are equipped with muscle cells (LMCs), which exhibit spontaneous contraction, whose molecular machinery is still undetermined. Hypothesizing that spontaneous contraction might involve hyperpolarization-activated cyclic nucleotide-gated (HCN) channels in lymphatic LMCs, diaphragmatic specimens, including spontaneously contracting lymphatics, were excised from 33 anesthetized rats, moved to a perfusion chamber containing HEPES-Tyrode's solution, and treated with HCN channels inhibitors cesium chloride (CsCl), ivabradine, and ZD-7288. Compared with control, exposure to 10 mM CsCl reduced (−65%, n = 13, P < 0.01) the contraction frequency (FL) and increased end-diastolic diameter (DL-d, +7.3%, P < 0.01) without changes in end-systolic diameter (DL-s). Ivabradine (300 μM) abolished contraction and increased DL-d (−14%, n = 10, P < 0.01) or caused an incomplete inhibition of FL ( n = 3, P < 0.01), leaving DL-d and DL-s unaltered. ZD-7288 (200 μM) completely ( n = 12, P < 0.01) abolished FL, while DL-d decreased to 90.9 ± 2.7% of control. HCN gene expression and immunostaining confirmed the presence of HCN1-4 channel isoforms, likely arranged in different configurations, in LMCs. Hence, all together, data suggest that HCN channels might play an important role in affecting contraction frequency of LMCs.

scholarly journals Simulation and calculation of the contribution of hyperpolarization-activated cyclic nucleotide-gated channels to action potentials

2016 ◽  
Vol 68 (1) ◽  
pp. 217-224
Author(s):  
Liping Liao ◽  
Xianguang Lin ◽  
Jielin Hu ◽  
Xin Wu ◽  
Xiaofei Yang ◽  
...  
Keyword(s):  
Membrane Potential ◽  
Action Potential ◽  
Cyclic Nucleotide ◽  
Ganglion Cells ◽  
Recovery Phase ◽  
Hcn Channels ◽  
Action Potential Generation ◽  
Hcn Channel ◽  
Potential Generation ◽  
Cyclic Nucleotide Gated Channels

The hyperpolarization-activated cyclic nucleotide-gated (HCN) channel, which mediates the influx of cations, has an important role in action potential generation. In this article, we describe the contribution of the HCN channel to action potential generation. We simulated several common ion channels in neuron membranes based on data from rat dorsal root ganglion cells and modeled the action potential. The ion channel models employed in this paper were based on the Markov model. After modifying and calibrating these models, we compared the simulated action potential curves under the presence and absence of an HCN channel and calculated that the proportional contribution of the HCN channel in the potential recovery phase was 33.39%. This result indicates that the HCN channel is critical in assisting membrane potential recovery from a hyperpolarized state to a resting state. Furthermore, we showed how the HCN channel modifies the firing of the action potential using mathematic modeling. Our results indicated that although the loss of the HCN channel made recovery of the membrane potential more difficult from the most negative point to resting in comparison with the control, the firing rate of the action potential increased in certain circumstances. We present a novel explanation for the HCN channels? mechanism in neuron action potential generation using mathematical models.

scholarly journals Cyclic nucleotide-regulated channels (version 2019.4) in the IUPHAR/BPS Guide to Pharmacology Database

2019 ◽  
Vol 2019 (4) ◽  
Author(s):  
Elvir Becirovic ◽  
Martin Biel ◽  
Verena Hammelmann ◽  
Franz Hofmann ◽  
U. Benjamin Kaupp
Keyword(s):  
Cyclic Gmp ◽  
Cyclic Nucleotides ◽  
Cyclic Nucleotide ◽  
Cardiac Cells ◽  
Cation Channels ◽  
Sensory Cells ◽  
Hcn Channels ◽  
Excitable Cells ◽  
C Terminus ◽  
Voltage Gated Ion Channels

Cyclic nucleotide-gated (CNG) channels are responsible for signalling in the primary sensory cells of the vertebrate visual and olfactory systems.CNG channels are voltage-independent cation channels formed as tetramers. Each subunit has 6TM, with the pore-forming domain between TM5 and TM6. CNG channels were first found in rod photoreceptors [69, 98], where light signals through rhodopsin and transducin to stimulate phosphodiesterase and reduce intracellular cyclic GMP level. This results in a closure of CNG channels and a reduced ‘dark current’. Similar channels were found in the cilia of olfactory neurons [153] and the pineal gland [60]. The cyclic nucleotides bind to a domain in the C terminus of the subunit protein: other channels directly binding cyclic nucleotides include HCN, eag and certain plant potassium channels.Hyperpolarisation-activated, cyclic nucleotide-gated (HCN)The hyperpolarisation-activated, cyclic nucleotide-gated (HCN) channels are cation channels that are activated by hyperpolarisation at voltages negative to ~-50 mV. The cyclic nucleotides cyclic AMP and cyclic GMP directly activate the channels and shift the activation curves of HCN channels to more positive voltages, thereby enhancing channel activity. HCN channels underlie pacemaker currents found in many excitable cells including cardiac cells and neurons [56, 164]. In native cells, these currents have a variety of names, such as Ih, Iq and If. The four known HCN channels have six transmembrane domains and form tetramers. It is believed that the channels can form heteromers with each other, as has been shown for HCN1 and HCN4 [2]. High resolution structural studies of CNG and HCN channels has provided insight into the the gating processes of these channels [117, 121]. A standardised nomenclature for CNG and HCN channels has been proposed by the NC-IUPHAR subcommittee on voltage-gated ion channels [88].

scholarly journals The HCN domain couples voltage gating and cAMP response in hyperpolarization-activated cyclic nucleotide-gated channels

eLife ◽  
2019 ◽  
Vol 8 ◽  
Author(s):  
Alessandro Porro ◽  
Andrea Saponaro ◽  
Federica Gasparri ◽  
Daniel Bauer ◽  
Christine Gross ◽  
...  
Keyword(s):  
Cyclic Nucleotide ◽  
Channel Gating ◽  
Hcn Channels ◽  
Structural Mechanism ◽  
Cyclic Nucleotide Gated Channels ◽  
Channel Opening ◽  
Mode Of Operation ◽  
Voltage Dependent ◽  
Upward Displacement ◽  
Voltage Sensing Domain

Hyperpolarization-activated cyclic nucleotide-gated (HCN) channels control spontaneous electrical activity in heart and brain. Binding of cAMP to the cyclic nucleotide-binding domain (CNBD) facilitates channel opening by relieving a tonic inhibition exerted by the CNBD. Despite high resolution structures of the HCN1 channel in the cAMP bound and unbound states, the structural mechanism coupling ligand binding to channel gating is unknown. Here we show that the recently identified helical HCN-domain (HCND) mechanically couples the CNBD and channel voltage sensing domain (VSD), possibly acting as a sliding crank that converts the planar rotational movement of the CNBD into a rotational upward displacement of the VSD. This mode of operation and its impact on channel gating are confirmed by computational and experimental data showing that disruption of critical contacts between the three domains affects cAMP- and voltage-dependent gating in three HCN isoforms.

scholarly journals Roles of Microglial Ion Channel in Neurodegenerative Diseases

2021 ◽  
Vol 10 (6) ◽  
pp. 1239
Author(s):  
Alexandru Cojocaru ◽  
Emilia Burada ◽  
Adrian-Tudor Bălșeanu ◽  
Alexandru-Florian Deftu ◽  
Bogdan Cătălin ◽  
...  
Keyword(s):  
Ion Channels ◽  
Neurodegenerative Diseases ◽  
Excitable Cells ◽  
Proton Channels ◽  
Voltage Gated ◽  
Cellular Processes ◽  
Pathological Conditions ◽  
The Common ◽  
Transient Receptor ◽  
The Impact

As the average age and life expectancy increases, the incidence of both acute and chronic central nervous system (CNS) pathologies will increase. Understanding mechanisms underlying neuroinflammation as the common feature of any neurodegenerative pathology, we can exploit the pharmacology of cell specific ion channels to improve the outcome of many CNS diseases. As the main cellular player of neuroinflammation, microglia play a central role in this process. Although microglia are considered non-excitable cells, they express a variety of ion channels under both physiological and pathological conditions that seem to be involved in a plethora of cellular processes. Here, we discuss the impact of modulating microglia voltage-gated, potential transient receptor, chloride and proton channels on microglial proliferation, migration, and phagocytosis in neurodegenerative diseases.

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