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1
Brandt, Mathias C., Jeannette Endres-Becker, Naufal Zagidullin, Lukas J. Motloch, Fikret Er, Dennis Rottlaender, Guido Michels, Stefan Herzig, and Uta C. Hoppe. "Effects of KCNE2 on HCN isoforms: distinct modulation of membrane expression and single channel properties." American Journal of Physiology-Heart and Circulatory Physiology 297, no. 1 (July 2009): H355—H363. http://dx.doi.org/10.1152/ajpheart.00154.2009.
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Hyperpolarization-activated cation (HCN) channels give rise to an inward current with similar but not identical characteristics compared with the pacemaker current ( If), suggesting that HCN channel function is modulated by regulatory β-subunits in native tissue. KCNE2 has been proposed to serve as a β-subunit of HCN channels; however, available data remain contradictory. To further clarify this situation, we therefore analyzed the effect of KCNE2 on whole cell currents, single channel properties, and membrane protein expression of all cardiac HCN isoforms in the CHO cell system. On the whole cell level, current densities of all HCN isoforms were significantly increased by KCNE2 without altering voltage dependence or current reversal. While these results correlated well with the KCNE2-mediated 2.2-fold and 1.6-fold increases of membrane protein levels of HCN2 and HCN4, respectively, no effect of KCNE2 on HCN1 expression was obtained. All HCN subtypes displayed faster activation kinetics upon coexpression with KCNE2. Most importantly, for the first time, we demonstrated modulation of single channel function by KCNE2, thus supporting direct functional interaction with HCN subunits. In the presence of KCNE2, the single channel amplitudes and conductance of HCN1, HCN2, and HCN4 were significantly increased versus control recordings. Mean open time was significantly increased in cells coexpressing HCN2 + KCNE2, whereas it was unaffected in HCN1 + KCNE2 cotransfected cells and reduced in HCN4 + KCNE2 cotransfected cells compared with the respective HCN subunits alone. Thus, we demonstrate KCNE2-mediated distinct effects on HCN membrane expression and direct functional modulation of HCN isoforms, further supporting that KCNE2 surves as a regulatory β-subunit of HCN channels.
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Männikkö, Roope, Shilpi Pandey, H. Peter Larsson, and Fredrik Elinder. "Hysteresis in the Voltage Dependence of HCN Channels." Journal of General Physiology 125, no. 3 (February 14, 2005): 305–26. http://dx.doi.org/10.1085/jgp.200409130.
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Hyperpolarization-activated, cyclic nucleotide-gated (HCN) ion channels are important for rhythmic activity in the brain and in the heart. In this study, using ionic and gating current measurements, we show that cloned spHCN channels undergo a hysteresis in their voltage dependence during normal gating. For example, both the gating charge versus voltage curve, Q(V), and the conductance versus voltage curve, G(V), are shifted by about +60 mV when measured from a hyperpolarized holding potential compared with a depolarized holding potential. In addition, the kinetics of the tail current and the activation current change in parallel to the voltage shifts of the Q(V) and G(V) curves. Mammalian HCN1 channels display similar effects in their ionic currents, suggesting that the mammalian HCN channels also undergo voltage hysteresis. We propose a model in which HCN channels transit between two modes. The voltage dependence in the two modes is shifted relative to each other, and the occupancy of the two modes depends on the previous activation of the channel. The shifts in the voltage dependence are fast (τ ≈ 100 ms) and are not accompanied by any apparent inactivation. In HCN1 channels, the shift in voltage dependence is slower in a 100 mM K extracellular solution compared with a 1 mM K solution. Based on these findings, we suggest that molecular conformations similar to slow (C-type) inactivation of K channels underlie voltage hysteresis in HCN channels. The voltage hysteresis results in HCN channels displaying different voltage dependences during different phases in the pacemaker cycle. Computer simulations suggest that voltage hysteresis in HCN channels decreases the risk of arrhythmia in pacemaker cells.
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Lieu, Deborah K., Yau Chi Chan, Chu Pak Lau, Hung Fat Tse, Chung Wah Siu, and Ronald A. Li. "Overexpression of HCN-encoded pacemaker current silences bioartificial pacemakers." Heart Rhythm 5, no. 9 (September 2008): 1310–17. http://dx.doi.org/10.1016/j.hrthm.2008.05.010.
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Dekker, John P., and Gary Yellen. "Cooperative Gating between Single HCN Pacemaker Channels." Journal of General Physiology 128, no. 5 (October 16, 2006): 561–67. http://dx.doi.org/10.1085/jgp.200609599.
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HCN pacemaker channels (If, Iq, or Ih) play a fundamental role in the physiology of many excitable cell types, including cardiac myocytes and central neurons. While cloned HCN channels have been studied extensively in macroscopic patch clamp experiments, their extremely small conductance has precluded single channel analysis to date. Nevertheless, there remain fundamental questions about HCN gating that can be resolved only at the single channel level. Here we present the first detailed single channel study of cloned mammalian HCN2. Excised patch clamp recordings revealed discrete hyperpolarization-activated, cAMP-sensitive channel openings with amplitudes of 150–230 fA in the activation voltage range. The average conductance of these openings was ∼1.5 pS at −120 mV in symmetrical 160 mM K+. Some traces with multiple channels showed unusual gating behavior, characterized by a variable long delay after a voltage step followed by runs of openings. Noise analysis on macroscopic currents revealed fluctuations whose magnitudes were systematically larger than predicted from the actual single channel current size, consistent with cooperativity between single HCN channels.
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Yang, Qizong, Pavlo Kuzyk, Igor Antonov, Caleb J. Bostwick, Andrea B. Kohn, Leonid L. Moroz, and Robert D. Hawkins. "Hyperpolarization-activated, cyclic nucleotide-gated cation channels in Aplysia: Contribution to classical conditioning." Proceedings of the National Academy of Sciences 112, no. 52 (December 14, 2015): 16030–35. http://dx.doi.org/10.1073/pnas.1501731113.
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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.
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Meuth, Sven G., Tatyana Kanyshkova, Patrick Meuth, Peter Landgraf, Thomas Munsch, Andreas Ludwig, Franz Hofmann, Hans-Christian Pape, and Thomas Budde. "Membrane Resting Potential of Thalamocortical Relay Neurons Is Shaped by the Interaction Among TASK3 and HCN2 Channels." Journal of Neurophysiology 96, no. 3 (September 2006): 1517–29. http://dx.doi.org/10.1152/jn.01212.2005.
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By combining molecular biological, electrophysiological, immunological, and computer modeling techniques, we here demonstrate a counterbalancing contribution of TASK channels, underlying hyperpolarizing K+ leak currents, and HCN channels, underlying depolarizing Ih, to the resting membrane potential of thalamocortical relay (TC) neurons. RT-PCR experiments revealed the expression of TASK1, TASK3, and HCN1–4. Quantitative determination of mRNA expression levels and immunocytochemical staining demonstrated that TASK3 and HCN2 channels represent the dominant thalamic isoforms and are coexpressed in TC neurons. Extracellular acidification, a standard procedure to inhibit TASK channels, blocked a TASK current masked by additional action on HCN channels. Only in the presence of the HCN blocker ZD7288 was the pH-sensitive component typical for a TASK current, i.e., outward rectification and current reversal at the K+ equilibrium potential. In a similar way extracellular acidification was able to shift the activity pattern of TC neurons from burst to tonic firing only during block of Ih or genetic knock out of HCN channels. A single compartmental computer model of TC neurons simulated the counterbalancing influence of TASK and HCN on the resting membrane potential. It is concluded that TASK3 and HCN2 channels stabilize the membrane potential by a mutual functional interaction, that the most efficient way to regulate the membrane potential of TC neurons is the converse modulation of TASK and HCN channels, and that TC neurons are potentially more resistant to insults accompanied by extracellular pH shifts in comparison to other CNS regions.
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Accili, E. A., C. Proenza, M. Baruscotti, and D. DiFrancesco. "From Funny Current to HCN Channels: 20 Years of Excitation." Physiology 17, no. 1 (February 2002): 32–37. http://dx.doi.org/10.1152/physiologyonline.2002.17.1.32.
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The “funny” (pacemaker) current has unusual characteristics, including activation on hyperpolarization, permeability to K+ and Na+, modulation by internal cAMP, and a tiny, single-channel conductance. In cardiac cells and neurons, pacemaker channels control repetitive activity and excitability. The recent cloning of HCN subunits provides new insight into the molecular basis for the funny channel properties.
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Li, Yu-Long, and Hong Zheng. "Angiotensin II-NADPH oxidase-derived superoxide mediates diabetes-attenuated cell excitability of aortic baroreceptor neurons." American Journal of Physiology-Cell Physiology 301, no. 6 (December 2011): C1368—C1377. http://dx.doi.org/10.1152/ajpcell.00214.2011.
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Overactivation of hyperpolarization-activated cyclic nucleotide-gated (HCN) channels is involved in diabetes-depressed excitability of aortic baroreceptor neurons in nodose ganglia. This involvement links to the autonomic dysfunction associated with high morbidity and mortality in diabetic patients. The present study examined the effects of an angiotensin II type I receptor (AT1R) antagonist (losartan), a NADPH oxidase inhibitor (apocynin), and a superoxide dismutase mimetic (tempol) on the enhanced HCN currents and attenuated cell excitability in diabetic nodose neurons. In sham and streptozotocin-induced type 1 diabetic rats, HCN currents and cell excitability of aortic baroreceptor neurons were recorded by the whole cell patch-clamp technique. The angiotensin II level in nodose ganglia from diabetic rats was higher than that from sham rats (101.6 ± 4.8 vs. 38.9 ± 4.2 pg/mg protein, P < 0.05). Single-cell RT-PCR, Western blot, immunofluorescence staining, and chemiluminescence data showed that mRNA and protein expression of AT1R, protein expression of NADPH oxidase components, and superoxide production in nodose neurons were increased in diabetic rats compared with those from sham rats. HCN current density was higher and cell excitability was lower in aortic baroreceptor neurons from diabetic rats than that from sham rats. Losartan (1 μM), apocynin (100 μM), and tempol (1 mM) normalized the enhanced HCN current density and increased the cell excitability in the aortic baroreceptor neurons of diabetic rats. These findings suggest that endogenous angiotensin II-NADPH oxidase-superoxide signaling contributes to the enhanced HCN currents and the depressed cell excitation in the aortic baroreceptor neurons of diabetic rats.
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Kelley, Craig, Salvador Dura-Bernal, Samuel A. Neymotin, Srdjan D. Antic, Nicholas T. Carnevale, Michele Migliore, and William W. Lytton. "Effects of Ih and TASK-like shunting current on dendritic impedance in layer 5 pyramidal-tract neurons." Journal of Neurophysiology 125, no. 4 (April 1, 2021): 1501–16. http://dx.doi.org/10.1152/jn.00015.2021.
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We simulated chirp current stimulation in the apical dendrites of 5 biophysically detailed multicompartment models of neocortical pyramidal tract neurons and found that a combination of HCN channels and TASK-like channels produced the best fit to experimental measurements of dendritic impedance. We then explored how HCN and TASK-like channels can shape the dendritic impedance as well as the voltage response to synaptic currents.
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Proenza, Catherine, and Gary Yellen. "Distinct Populations of HCN Pacemaker Channels Produce Voltage-dependent and Voltage-independent Currents." Journal of General Physiology 127, no. 2 (January 30, 2006): 183–90. http://dx.doi.org/10.1085/jgp.200509389.
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Hyperpolarization-activated HCN pacemaker channels are critical for the generation of spontaneous activity and the regulation of excitability in the heart and in many types of neurons. These channels produce both a voltage-dependent current (Ih) and a voltage-independent current (Iinst or VIC). In this study, we explored the molecular basis of the voltage-independent current. We found that for the spHCN isoform, VIC averaged ∼4% of the maximum HCN conductance that could be activated by hyperpolarization. Cyclic AMP increased the voltage-independent current in spHCN to ∼8% of maximum. In HCN2, VIC was ∼2% of the maximal current, and was little affected by cAMP. VIC in both spHCN and HCN2 was blocked rapidly both by ZD7288 (an HCN channel blocker that is thought to bind in the conduction pore) and by application of Cd2+ to channels containing an introduced cysteine in the pore (spHCN-464C or HCN2-436C). These results suggest that VIC flows through the main conduction pathway, down the central axis of the protein. We suspected that VIC simply represented a nonzero limiting open probability for HCN channels at positive voltages. Surprisingly, we found instead that the spHCN channels carrying VIC were not in rapid equilibrium with the channels carrying the voltage-dependent current, because they could be blocked independently; a single application of blocker at a depolarized potential essentially eliminated VIC with little change in Ih. Thus, VIC appears to be produced by a distinct population of HCN channels. This voltage-independent current could contribute significantly to the role of HCN channels in neurons and myocytes; VIC flowing through the channels at physiological potentials would tend to promote excitability by accelerating both depolarization and repolarization.
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Mishra, Poonam, and Rishikesh Narayanan. "High-conductance states and A-type K+ channels are potential regulators of the conductance-current balance triggered by HCN channels." Journal of Neurophysiology 113, no. 1 (January 1, 2015): 23–43. http://dx.doi.org/10.1152/jn.00601.2013.
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An increase in the hyperpolarization-activated cyclic nucleotide-gated (HCN) channel conductance reduces input resistance, whereas the consequent increase in the inward h current depolarizes the membrane. This results in a delicate and unique conductance-current balance triggered by the expression of HCN channels. In this study, we employ experimentally constrained, morphologically realistic, conductance-based models of hippocampal neurons to explore certain aspects of this conductance-current balance. First, we found that the inclusion of an experimentally determined gradient in A-type K+ conductance, but not in M-type K+ conductance, tilts the HCN conductance-current balance heavily in favor of conductance, thereby exerting an overall restorative influence on neural excitability. Next, motivated by the well-established modulation of neuronal excitability by synaptically driven high-conductance states observed under in vivo conditions, we inserted thousands of excitatory and inhibitory synapses with different somatodendritic distributions. We measured the efficacy of HCN channels, independently and in conjunction with other channels, in altering resting membrane potential (RMP) and input resistance ( Rin) when the neuron received randomized or rhythmic synaptic bombardments through variable numbers of synaptic inputs. We found that the impact of HCN channels on average RMP, Rin, firing frequency, and peak-to-peak voltage response was severely weakened under high-conductance states, with the impinging synaptic drive playing a dominant role in regulating these measurements. Our results suggest that the debate on the role of HCN channels in altering excitability should encompass physiological and pathophysiological neuronal states under in vivo conditions and the spatiotemporal interactions of HCN channels with other channels.
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Biel, Martin, Christian Wahl-Schott, Stylianos Michalakis, and Xiangang Zong. "Hyperpolarization-Activated Cation Channels: From Genes to Function." Physiological Reviews 89, no. 3 (July 2009): 847–85. http://dx.doi.org/10.1152/physrev.00029.2008.
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Hyperpolarization-activated cyclic nucleotide-gated (HCN) channels comprise a small subfamily of proteins within the superfamily of pore-loop cation channels. In mammals, the HCN channel family comprises four members (HCN1-4) that are expressed in heart and nervous system. The current produced by HCN channels has been known as Ih (or If or Iq). Ih has also been designated as pacemaker current, because it plays a key role in controlling rhythmic activity of cardiac pacemaker cells and spontaneously firing neurons. Extensive studies over the last decade have provided convincing evidence that Ih is also involved in a number of basic physiological processes that are not directly associated with rhythmicity. Examples for these non-pacemaking functions of Ih are the determination of the resting membrane potential, dendritic integration, synaptic transmission, and learning. In this review we summarize recent insights into the structure, function, and cellular regulation of HCN channels. We also discuss in detail the different aspects of HCN channel physiology in the heart and nervous system. To this end, evidence on the role of individual HCN channel types arising from the analysis of HCN knockout mouse models is discussed. Finally, we provide an overview of the impact of HCN channels on the pathogenesis of several diseases and discuss recent attempts to establish HCN channels as drug targets.
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Zhang, Yi, Yunfeng Liu, Jihong Qu, Alexandre Hardy, Nina Zhang, Jingyu Diao, Paul J. Strijbos, et al. "Functional characterization of hyperpolarization-activated cyclic nucleotide-gated channels in rat pancreatic β cells." Journal of Endocrinology 203, no. 1 (August 4, 2009): 45–53. http://dx.doi.org/10.1677/joe-09-0068.
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Hyperpolarization-activated cyclic nucleotide-gated (HCN) channels regulate pacemaker activity in some cardiac cells and neurons. In the present study, we have identified the presence of HCN channels in pancreatic β-cells. We then examined the functional characterization of these channels in β-cells via modulating HCN channel activity genetically and pharmacologically. Voltage-clamp experiments showed that over-expression of HCN2 in rat β-cells significantly increased HCN current (Ih), whereas expression of dominant-negative HCN2 (HCN2-AYA) completely suppressed endogenous Ih. Compared to control β-cells, over-expression of Ih increased insulin secretion at 2.8 mmol/l glucose. However, suppression of Ih did not affect insulin secretion at both 2.8 and 11.1 mmol/l glucose. Current-clamp measurements revealed that HCN2 over-expression significantly reduced β-cell membrane input resistance (Rin), and resulted in a less-hyperpolarizing membrane response to the currents injected into the cell. Conversely, dominant negative HCN2-AYA expression led to a substantial increase of Rin, which was associated with a more hyperpolarizing membrane response to the currents injected. Remarkably, under low extracellular potassium conditions (2.5 mmol/l K+), suppression of Ih resulted in increased membrane hyperpolarization and decreased insulin secretion. We conclude that Ih in β-cells possess the potential to modulate β-cell membrane potential and insulin secretion under hypokalemic conditions.
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He, Jin-Ting, Xiao-Yan Li, Xin Zhao, and Xiaoliang Liu. "Hyperpolarization-activated and cyclic nucleotide-gated channel proteins as emerging new targets in neuropathic pain." Reviews in the Neurosciences 30, no. 6 (July 26, 2019): 639–49. http://dx.doi.org/10.1515/revneuro-2018-0094.
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Abstract Hyperpolarization-activated and cyclic nucleotide-gated (HCN) channels are activated during hyperpolarization, and there is an inward flow of current, which is termed as hyperpolarization-activated current, Ih. Initially, these channels were identified on the pacemaker cells of the heart. Nowadays, these are identified on different regions of the nervous system, including peripheral nerves, dorsal root ganglia, dorsal horns, and different parts of the brain. There are four different types of HCN channels (HCN1–HCN4); however, HCN1 and HCN2 are more prominent. A large number of studies have shown that peripheral nerve injury increases the amplitude of Ih current in the neurons of the spinal cord and the brain. Moreover, there is an increase in the expression of HCN1 and HCN2 protein channels in peripheral axons and the spinal cord and brain regions in experimental models of nerve injury. Studies have also documented the pain-attenuating actions of selective HCN inhibitors, such as ivabradine and ZD7288. Moreover, certain drugs with additional HCN-blocking activities have also shown pain-attenuating actions in different pain models. There have been few studies documenting the relationship of HCN channels with other mediators of pain. Nevertheless, it may be proposed that the HCN channel activity is modulated by endogenous opioids and cyclo-oxygenase-2, whereas the activation of these channels may modulate the actions of substance P and the expression of spinal N-methyl-D-aspartate receptor subunit 2B to modulate pain. The present review describes the role and mechanisms of HCN ion channels in the development of neuropathic pain.
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Gao, Weihua, Zhuocheng Su, Qinglian Liu, and Lei Zhou. "State-dependent and site-directed photodynamic transformation of HCN2 channel by singlet oxygen." Journal of General Physiology 143, no. 5 (April 14, 2014): 633–44. http://dx.doi.org/10.1085/jgp.201311112.
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Singlet oxygen (1O2), which is generated through metabolic reactions and oxidizes numerous biological molecules, has been a useful tool in basic research and clinical practice. However, its role as a signaling factor, as well as a mechanistic understanding of the oxidation process, remains poorly understood. Here, we show that hyperpolarization-activated, cAMP-gated (HCN) channels–which conduct the hyperpolarization-activated current (Ih) and the voltage-insensitive instantaneous current (Iinst), and contribute to diverse physiological functions including learning and memory, cardiac pacemaking, and the sensation of pain–are subject to modification by 1O2. To increase the site specificity of 1O2 generation, we used fluorescein-conjugated cAMP, which specifically binds to HCN channels, or a chimeric channel in which an in-frame 1O2 generator (SOG) protein was fused to the HCN C terminus. Millisecond laser pulses reduced Ih current amplitude, slowed channel deactivation, and enhanced Iinst current. The modification of HCN channel function is a photodynamic process that involves 1O2, as supported by the dependence on dissolved oxygen in solutions, the inhibitory effect by a 1O2 scavenger, and the results with the HCN2-SOG fusion protein. Intriguingly, 1O2 modification of the HCN2 channel is state dependent: laser pulses applied to open channels mainly slow down deactivation and increase Iinst, whereas for the closed channels, 1O2 modification mainly reduced Ih amplitude. We identified a histidine residue (H434 in S6) near the activation gate in the pore critical for 1O2 modulation of HCN function. Alanine replacement of H434 abolished the delay in channel deactivation and the generation of Iinst induced by photodynamic modification. Our study provides new insights into the instantaneous current conducted by HCN channels, showing that modifications to the region close to the intracellular gate underlie the expression of Iinst, and establishes a well-defined model for studying 1O2 modifications at the molecular level.
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Weerasinghe, Dinushi, Parvathi Menon, and Steve Vucic. "Hyperpolarization-activated cyclic-nucleotide-gated channels potentially modulate axonal excitability at different thresholds." Journal of Neurophysiology 118, no. 6 (December 1, 2017): 3044–50. http://dx.doi.org/10.1152/jn.00576.2017.
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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.
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Au, Ka-Wing, Chung-Wah Siu, Chu-Pak Lau, Hung-Fat Tse, and Ronald A. Li. "Structural and functional determinants in the S5-P region of HCN-encoded pacemaker channels revealed by cysteine-scanning substitutions." American Journal of Physiology-Cell Physiology 294, no. 1 (January 2008): C136—C144. http://dx.doi.org/10.1152/ajpcell.00340.2007.
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Hyperpolarization-activated cyclic nucleotide-modulated (HCN) channels are responsible for the membrane pacemaker current that underlies the spontaneous generation of bioelectrical rhythms. However, their structure-function relationship is poorly understood. Previously, we identified several pore residues that influence HCN gating properties and proposed a pore-to-gate mechanism. Here, we systematically introduced cysteine-scanning substitutions into the descending portion of the P loop (residues 339–345) of HCN1-R (where R is resistance to sulfhydryl-reactive agents) channels, in which all endogenous cysteines except C303 have been removed or replaced. F339C, K340C, A341C, M342C, S343C, and M345C did not produce functional currents. Interestingly, the loss of function phenotype of F339C could be rescued by the reducing agent dithiothreitol (DTT). H344C but not HCN1-R and DTT-treated F339C channels were sensitive to blockade by divalent Cd2+ (current with 100 μM Cd2+/control current at −140 mV = 67.6 ± 2.9%, 109.3 ± 3.1%, and 103.8 ± 1.7%, respectively). Externally applied methanethiosulfate ethylammonium, a covalent sulfhydryl-reactive compound, irreversibly modified H344C by reducing the current at −140 mV (to 43.7 ± 6.5%), causing a hyperpolarizing steady-state activation shift (change in half-activation voltage: ∼6 mV) and decelerated gating kinetics (by up to 3-fold). Based on these results, we conclude that pore residues 339–345 are important determinants of the structure-function properties of HCN channels and that the side chain of H344 is externally accessible.
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Radionov, V. P., and V. K. Kiseliov. "PHENOMENON OF PULSE LASING BIFURCATION IN THE ALTERNATING CURRENT PUMPED HCN-LASER." Telecommunications and Radio Engineering 69, no. 14 (2010): 1293–99. http://dx.doi.org/10.1615/telecomradeng.v69.i14.100.
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Shimatani, Yoshimitsu, Hiroyuki Nodera, Yusuke Osaki, Chimeglkham Banzrai, Kazuhiro Takayasu, Sachiko Endo, Yoshiko Shibuta, and Ryuji Kaji. "Upregulation of axonal HCN current by methylglyoxal: Potential association with diabetic polyneuropathy." Clinical Neurophysiology 126, no. 11 (November 2015): 2226–32. http://dx.doi.org/10.1016/j.clinph.2015.02.058.
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Hassinen, Minna, Jaakko Haverinen, and Matti Vornanen. "Small functional If current in sinoatrial pacemaker cells of the brown trout (Salmo trutta fario) heart despite strong expression of HCN channel transcripts." American Journal of Physiology-Regulatory, Integrative and Comparative Physiology 313, no. 6 (December 1, 2017): R711—R722. http://dx.doi.org/10.1152/ajpregu.00227.2017.
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Funny current ( If), formed by hyperpolarization-activated cyclic nucleotide-gated channels (HCN channels), is supposed to be crucial for the membrane clock regulating the cardiac pacemaker mechanism. We examined the presence and activity of HCN channels in the brown trout ( Salmo trutta fario) sinoatrial (SA) pacemaker cells and their putative role in heart rate ( fH) regulation. Six HCN transcripts (HCN1, HCN2a, HCN2ba, HCN2bb, HCN3, and HCN4) were expressed in the brown trout heart. The total HCN transcript abundance was 4.0 and 4.9 times higher in SA pacemaker tissue than in atrium and ventricle, respectively. In the SA pacemaker, HCN3 and HCN4 were the main isoforms representing 35.8 ± 2.7 and 25.0 ± 1.5%, respectively, of the total HCN transcripts. Only a small If with a mean current density of −1.2 ± 0.37 pA/pF at −140 mV was found in 4 pacemaker cells out of 16 spontaneously beating cells examined, despite the optimization of recording conditions for If activity. If was not found in any of the 24 atrial myocytes and 21 ventricular myocytes examined. HCN4 coexpressed with the MinK-related peptide 1 (MiRP1) β-subunit in CHO cells generated large If currents. In contrast, HCN3 (+MiRP1) failed to produce If in the same expression system. Cs+ (2 mM), which blocked 84 ± 12% of the native If, reversibly reduced fH 19.2 ± 3.6% of the excised multicellular pacemaker tissue from 53 ± 5 to 44 ± 5 beats/min ( P < 0.05). However, this effect was probably due to the reduction of IKr, which was also inhibited (63.5 ± 4.6%) by Cs+. These results strongly suggest that fH regulation in the brown trout heart is largely independent on If.
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Spinelli, Valentina, Laura Sartiani, Alessandro Mugelli, Maria Novella Romanelli, and Elisabetta Cerbai. "Hyperpolarization-activated cyclic-nucleotide-gated channels: pathophysiological, developmental, and pharmacological insights into their function in cellular excitability." Canadian Journal of Physiology and Pharmacology 96, no. 10 (October 2018): 977–84. http://dx.doi.org/10.1139/cjpp-2018-0115.
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The hyperpolarization-activated cyclic-nucleotide-gated (HCN) proteins are voltage-dependent ion channels, conducting both Na+ and K+, blocked by millimolar concentrations of extracellular Cs+ and modulated by cyclic nucleotides (mainly cAMP) that contribute crucially to the pacemaker activity in cardiac nodal cells and subsidiary pacemakers. Over the last decades, much attention has focused on HCN current, If, in non-pacemaker cardiac cells and its potential role in triggering arrhythmias. In fact, in addition to pacemakers, HCN current is constitutively present in the human atria and has long been proposed to sustain atrial arrhythmias associated to different cardiac pathologies or triggered by various modulatory signals (catecholamines, serotonin, natriuretic peptides). An atypical If occurs in diseased ventricular cardiomyocytes, its amplitude being linearly related to the severity of cardiac hypertrophy. The properties of atrial and ventricular If and its modulation by pharmacological interventions has been object of intense study, including the synthesis and characterization of new compounds able to block preferentially HCN1, HCN2, or HCN4 isoforms. Altogether, clues emerge for opportunities of future pharmacological strategies exploiting the unique properties of this channel family: the prevalence of different HCN subtypes in organs and tissues, the possibility to target HCN gain- or loss-of-function associated with disease, the feasibility of novel isoform-selective drugs, as well as the discovery of HCN-mediated effects for old medicines.
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Marmoy, Oliver R., Paul L. Furlong, and Christopher E. G. Moore. "Upper and lower limb motor axons demonstrate differential excitability and accommodation to strong hyperpolarizing currents during induced hyperthermia." Journal of Neurophysiology 121, no. 6 (June 1, 2019): 2061–70. http://dx.doi.org/10.1152/jn.00464.2018.
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Length-dependent peripheral neuropathy typically involves the insidious onset of sensory loss in the lower limbs before later progressing proximally. Recent evidence proposes hyperpolarization-activated cyclic nucleotide-gated (HCN) channels as dysfunctional in rodent models of peripheral neuropathy, and therefore differential expression of HCN channels in the lower limbs was hypothesized as a pathophysiological mechanism accounting for the pattern of symptomatology within this study. We studied six healthy participants, using motor axon excitability including strong and long [−70% and −100% hyperpolarizing threshold electrotonus (TEh)] hyperpolarizing currents to preferably study HCN channel function from the median and tibial nerves from high (40%) and low (20%) threshold. This was recorded at normothermia (~32°C) and then repeated during hyperthermia (~40°C) as an artificial hyperpolarizing axon stress. Significant differences between recovery cycle, superexcitability, accommodation to small depolarizing currents, and alterations in late stages of the inward-rectifying currents of strongest (−70% and −100% TEh) currents were observed in the lower limbs during hyperthermia. We demonstrate differences in late IH current flow, which implies higher expression of HCN channel isoforms. The findings also indicate their potential inference in the symptomatology of length-dependent peripheral neuropathies and may be a unique target for minimizing symptomatology and pathogenesis in acquired disease. NEW & NOTEWORTHY This study demonstrates nerve excitability differences between the upper and lower limbs during hyperthermia, an experimentally induced axonal stress. The findings indicate that there is differential expression of slow hyperpolarization-activated cyclic nucleotide-gated (HCN) channel isoforms between the upper and lower limbs, which was demonstrated through strong, long hyperpolarizing currents during hyperthermia. Such mechanisms may underlie postural control but render the lower limbs susceptible to dysfunction in disease states.
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Albertson, Asher J., Sidney B. Williams, and John J. Hablitz. "Regulation of epileptiform discharges in rat neocortex by HCN channels." Journal of Neurophysiology 110, no. 8 (October 15, 2013): 1733–43. http://dx.doi.org/10.1152/jn.00955.2012.
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Hyperpolarization-activated, cyclic nucleotide-gated, nonspecific cation (HCN) channels have a well-characterized role in regulation of cellular excitability and network activity. The role of these channels in control of epileptiform discharges is less thoroughly understood. This is especially pertinent given the altered HCN channel expression in epilepsy. We hypothesized that inhibition of HCN channels would enhance bicuculline-induced epileptiform discharges. Whole cell recordings were obtained from layer (L)2/3 and L5 pyramidal neurons and L1 and L5 GABAergic interneurons. In the presence of bicuculline (10 μM), HCN channel inhibition with ZD 7288 (20 μM) significantly increased the magnitude (defined as area) of evoked epileptiform events in both L2/3 and L5 neurons. We recorded activity associated with epileptiform discharges in L1 and L5 interneurons to test the hypothesis that HCN channels regulate excitatory synaptic inputs differently in interneurons versus pyramidal neurons. HCN channel inhibition increased the magnitude of epileptiform events in both L1 and L5 interneurons. The increased magnitude of epileptiform events in both pyramidal cells and interneurons was due to an increase in network activity, since holding cells at depolarized potentials under voltage-clamp conditions to minimize HCN channel opening did not prevent enhancement in the presence of ZD 7288. In neurons recorded with ZD 7288-containing pipettes, bath application of the noninactivating inward cationic current ( Ih) antagonist still produced increases in epileptiform responses. These results show that epileptiform discharges in disinhibited rat neocortex are modulated by HCN channels.
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Boychuk, Jeffery A., and G. Campbell Teskey. "Loss of HCN channel mediated Ih current following seizures accounts for movement dysfunction." Channels 11, no. 3 (December 2, 2016): 176–77. http://dx.doi.org/10.1080/19336950.2016.1256517.
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Osaki, Yusuke, Hiroyuki Nodera, Chimeglkham Banzrai, Sachiko Endo, Hirokazu Takayasu, Atsuko Mori, Yoshimitsu Shimatani, and Ryuji Kaji. "Effects of anesthetic agents on in vivo axonal HCN current in normal mice." Clinical Neurophysiology 126, no. 10 (October 2015): 2033–39. http://dx.doi.org/10.1016/j.clinph.2014.12.025.
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VARGHESE, A., E. TENBROEK, J. COLESJR, and D. SIGG. "Endogenous channels in HEK cells and potential roles in HCN ionic current measurements." Progress in Biophysics and Molecular Biology 90, no. 1-3 (January 2006): 26–37. http://dx.doi.org/10.1016/j.pbiomolbio.2005.05.002.
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Liang, Qiansheng, Le Yang, Zhaohua Wang, Sufang Huang, Shusheng Li, and Guangtian Yang. "Tanshinone IIA Selectively Enhances Hyperpolarization-Activated Cyclic Nucleotide–Modulated (HCN) Channel Instantaneous Current." Journal of Pharmacological Sciences 110, no. 3 (2009): 381–88. http://dx.doi.org/10.1254/jphs.08334fp.
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Tomlinson, Susan, David Burke, Mike Hanna, Martin Koltzenburg, and Hugh Bostock. "In vivo assessment of HCN channel current (I h ) in human motor axons." Muscle & Nerve 41, no. 2 (October 7, 2009): 247–56. http://dx.doi.org/10.1002/mus.21482.
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Santoro, Bina, and Mala M. Shah. "Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels as Drug Targets for Neurological Disorders." Annual Review of Pharmacology and Toxicology 60, no. 1 (January 6, 2020): 109–31. http://dx.doi.org/10.1146/annurev-pharmtox-010919-023356.
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The hyperpolarization-activated cyclic nucleotide-gated (HCN) channels are voltage-gated ion channels that critically modulate neuronal activity. Four HCN subunits ( HCN1–4) have been cloned, each having a unique expression profile and distinctive effects on neuronal excitability within the brain. Consistent with this, the expression and function of these subunits are altered in diverse ways in neurological disorders. Here, we review current knowledge on the structure and distribution of the individual HCN channel isoforms, their effects on neuronal activity under physiological conditions, and how their expression and function are altered in neurological disorders, particularly epilepsy, neuropathic pain, and affective disorders. We discuss the suitability of HCN channels as therapeutic targets and how drugs might be strategically designed to specifically act on particular isoforms. We conclude that medicines that target individual HCN isoforms and/or their auxiliary subunit, TRIP8b, may provide valuable means of treating distinct neurological conditions.
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Cho, Hyun-jung, John B. Furness, and Ernest A. Jennings. "Postnatal maturation of the hyperpolarization-activated cation current, Ih, in trigeminal sensory neurons." Journal of Neurophysiology 106, no. 4 (October 2011): 2045–56. http://dx.doi.org/10.1152/jn.00798.2010.
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Hyperpolarization-activated inward currents ( Ih) contribute to neuronal excitability in sensory neurons. Four subtypes of hyperpolarization-activated cyclic nucleotide-gated (HCN) channels generate Ih, with different activation kinetics and cAMP sensitivities. The aim of the present study was to examine the postnatal development of Ih and HCN channel subunits in trigeminal ganglion (TG) neurons. Ih was investigated in acutely dissociated TG neurons from rats aged between postnatal day (P)1 and P35 with whole cell patch-clamp electrophysiology. In voltage-clamp studies, Ih was activated by a series of hyperpolarizing voltage steps from −40 mV to −120 mV in −10-mV increments. Tail currents from a common voltage step (−100 mV) were used to determine Ih voltage dependence. Ih activation was faster in older rats and occurred at more depolarized potentials; the half-maximal activation voltage ( V1/2) changed from −89.4 mV (P1) to −81.6 mV (P35). In current-clamp studies, blocking Ih with ZD7288 caused membrane hyperpolarization and increases in action potential half-duration at all postnatal ages examined. ZD7288 also reduced the action potential firing frequency in multiple-firing neurons. Western blot analysis of the TG detected immunoreactive bands corresponding to all HCN subtypes. HCN1 and HCN2 band density increased with postnatal age, whereas the low-intensity HCN3 and moderate-intensity HCN4 bands were not changed. This study suggests that functional Ih are activated in rat trigeminal sensory neurons from P1 during postnatal development, have an increasing role with age, and modify neuronal excitability.
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Bucchi, Annalisa, Mirko Baruscotti, and Andrea Barbuti. "f/HCN channels: From a tiny current controlling cardiac pacemaking to a pleiotropic current all over the body." Progress in Biophysics and Molecular Biology 166 (November 2021): 1–2. http://dx.doi.org/10.1016/j.pbiomolbio.2021.10.001.
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Vemana, Sriharsha, Shilpi Pandey, and H. Peter Larsson. "S4 Movement in a Mammalian HCN Channel." Journal of General Physiology 123, no. 1 (December 15, 2003): 21–32. http://dx.doi.org/10.1085/jgp.200308916.
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Hyperpolarization-activated, cyclic nucleotide–gated ion channels (HCN) mediate an inward cation current that contributes to spontaneous rhythmic firing activity in the heart and the brain. HCN channels share sequence homology with depolarization-activated Kv channels, including six transmembrane domains and a positively charged S4 segment. S4 has been shown to function as the voltage sensor and to undergo a voltage-dependent movement in the Shaker K+ channel (a Kv channel) and in the spHCN channel (an HCN channel from sea urchin). However, it is still unknown whether S4 undergoes a similar movement in mammalian HCN channels. In this study, we used cysteine accessibility to determine whether there is voltage-dependent S4 movement in a mammalian HCN1 channel. Six cysteine mutations (R247C, T249C, I251C, S253C, L254C, and S261C) were used to assess S4 movement of the heterologously expressed HCN1 channel in Xenopus oocytes. We found a state-dependent accessibility for four S4 residues: T249C and S253C from the extracellular solution, and L254C and S261C from the internal solution. We conclude that S4 moves in a voltage-dependent manner in HCN1 channels, similar to its movement in the spHCN channel. This S4 movement suggests that the role of S4 as a voltage sensor is conserved in HCN channels. In addition, to determine the reason for the different cAMP modulation and the different voltage range of activation in spHCN channels compared with HCN1 channels, we constructed a COOH-terminal–deleted spHCN. This channel appeared to be similar to a COOH-terminal–deleted HCN1 channel, suggesting that the main functional differences between spHCN and HCN1 channels are due to differences in their COOH termini or in the interaction between the COOH terminus and the rest of the channel protein in spHCN channels compared with HCN1 channels.
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Shimizu, Morihiro, Xinya Mi, Futoshi Toyoda, Akiko Kojima, Wei-Guang Ding, Yutaka Fukushima, Mariko Omatsu-Kanbe, Hirotoshi Kitagawa, and Hiroshi Matsuura. "Propofol, an Anesthetic Agent, Inhibits HCN Channels through the Allosteric Modulation of the cAMP-Dependent Gating Mechanism." Biomolecules 12, no. 4 (April 12, 2022): 570. http://dx.doi.org/10.3390/biom12040570.
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Propofol is a broadly used intravenous anesthetic agent that can cause cardiovascular effects, including bradycardia and asystole. A possible mechanism for these effects is slowing cardiac pacemaker activity due to inhibition of the hyperpolarization-activated, cyclic nucleotide-gated (HCN) channels. However, it remains unclear how propofol affects the allosteric nature of the voltage- and cAMP-dependent gating mechanism in HCN channels. To address this aim, we investigated the effect of propofol on HCN channels (HCN4 and HCN2) in heterologous expression systems using a whole-cell patch clamp technique. The extracellular application of propofol substantially suppressed the maximum current at clinical concentrations. This was accompanied by a hyperpolarizing shift in the voltage dependence of channel opening. These effects were significantly attenuated by intracellular loading of cAMP, even after considering the current modification by cAMP in opposite directions. The differential degree of propofol effects in the presence and absence of cAMP was rationalized by an allosteric gating model for HCN channels, where we assumed that propofol affects allosteric couplings between the pore, voltage-sensor, and cyclic nucleotide-binding domain (CNBD). The model predicted that propofol enhanced autoinhibition of pore opening by unliganded CNBD, which was relieved by the activation of CNBD by cAMP. Taken together, these findings reveal that propofol acts as an allosteric modulator of cAMP-dependent gating in HCN channels, which may help us to better understand the clinical action of this anesthetic drug.
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Weng, Wubin, Marcus Aldén, and Zhongshan Li. "Simultaneous Quantitative Detection of HCN and C2H2 in Combustion Environment Using TDLAS." Processes 9, no. 11 (November 14, 2021): 2033. http://dx.doi.org/10.3390/pr9112033.
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Emission of nitrogen oxides (NOx) and soot particles during the combustion of biomass fuels and municipal solid waste is a major environmental issue. Hydrogen cyanide (HCN) and acetylene (C2H2) are important precursors of NOx and soot particles, respectively. In the current work, infrared tunable diode laser absorption spectroscopy (IR-TDLAS), as a non-intrusive in situ technique, was applied to quantitatively measure HCN and C2H2 in a combustion environment. The P(11e) line of the first overtone vibrational band v1 of HCN at 6484.78 cm−1 and the P(27e) line of the v1 + v3 combination band of C2H2 at 6484.03 cm−1 were selected. However, the infrared absorption of the ubiquitous water vapor in the combustion environment brings great uncertainty to the measurement. To obtain accurate temperature-dependent water spectra between 6483.8 and 6485.8 cm−1, a homogenous hot gas environment with controllable temperatures varying from 1100 to 1950 K provided by a laminar flame was employed to perform systematic IR-TDLAS measurements. By fitting the obtained water spectra, water interference to the HCN and C2H2 measurement was sufficiently mitigated and the concentrations of HCN and C2H2 were obtained. The technique was applied to simultaneously measure the temporally resolved release of HCN and C2H2 over burning nylon 66 strips in a hot oxidizing environment of 1790 K.
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Hawkins, Virginia E., Joanna M. Hawryluk, Ana C. Takakura, Anastasios V. Tzingounis, Thiago S. Moreira, and Daniel K. Mulkey. "HCN channels contribute to serotonergic modulation of ventral surface chemosensitive neurons and respiratory activity." Journal of Neurophysiology 113, no. 4 (February 15, 2015): 1195–205. http://dx.doi.org/10.1152/jn.00487.2014.
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Chemosensitive neurons in the retrotrapezoid nucleus (RTN) provide a CO2/H+-dependent drive to breathe and function as an integration center for the respiratory network, including serotonergic raphe neurons. We recently showed that serotonergic modulation of RTN chemoreceptors involved inhibition of KCNQ channels and activation of an unknown inward current. Hyperpolarization-activated cyclic-nucleotide-gated (HCN) channels are the molecular correlate of the hyperpolarization-activated inward current ( Ih) and have a high propensity for modulation by serotonin. To investigate whether HCN channels contribute to basal activity and serotonergic modulation of RTN chemoreceptors, we characterize resting activity and the effects of serotonin on RTN chemoreceptors in vitro and on respiratory activity of anesthetized rats in the presence or absence of blockers of KCNQ (XE991) and/or HCN (ZD7288, Cs+) channels. We found in vivo that bilateral RTN injections of ZD7288 increased respiratory activity and in vitro HCN channel blockade increased activity of RTN chemoreceptors under control conditions, but this was blunted by KCNQ channel inhibition. Furthermore, in vivo unilateral RTN injection of XE991 plus ZD7288 eliminated the serotonin response, and in vitro serotonin sensitivity was eliminated by application of XE991 and ZD7288 or SQ22536 (adenylate cyclase blocker). Serotonin-mediated activation of RTN chemoreceptors was blocked by a 5-HT7-receptor blocker and mimicked by a 5-HT7-receptor agonist. In addition, serotonin caused a depolarizing shift in the voltage-dependent activation of Ih. These results suggest that HCN channels contribute to resting chemoreceptor activity and that serotonin activates RTN chemoreceptors and breathing in part by a 5-HT7 receptor-dependent mechanism and downstream activation of Ih.
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Kim, Chung Sub, and Daniel Johnston. "A Possible Link Between HCN Channels and Depression." Chronic Stress 2 (January 2018): 247054701878778. http://dx.doi.org/10.1177/2470547018787781.
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Growing evidence suggests a possible link between hyperpolarization-activated cyclic nucleotide-gated nonselective cation (HCN) channels and depression. In a recent study published in Molecular Psychiatry, we first demonstrate that Ih (the membrane current mediated by HCN channels) and HCN1 protein expression were increased in dorsal, but not in ventral, CA1 region following chronic, but not acute stress. This upregulation of Ih was restricted to the perisomatic region of CA1 neurons and contributed to a reduction of neuronal excitability. A reduction of HCN1 protein expression in dorsal CA1 region before the onset of chronic unpredictable stress-induced depression was sufficient to provide resilient effects to chronic unpredictable stress. Furthermore, in vivo block of the sarcoplasmic/endoplasmic reticulum Ca2+-ATPase (SERCA) pumps, a manipulation known to increase intracellular calcium levels and upregulate Ih, produced anxiogenic-like behavior and an increase in Ih, similar to that observed in chronic unpredictable stress model of depression. Here, we share our view on (1) how the function and expression of HCN1 channels are changed in the brain in a subcellular region-specific manner during the development of depression and (2) how a reduction of HCN1 protein expression provides resilience to chronic stress.
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Ramasamy, Ramalakshmi, Alya AlObaidi, and Phillip Smith. "STABILIZING ROLE OF HCN CHANNELS ON POST-CAMP MECHANISMS OF DETRUSOR MYOCYTE CONTROL." Innovation in Aging 6, Supplement_1 (November 1, 2022): 664. http://dx.doi.org/10.1093/geroni/igac059.2448.
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Abstract Aging is associated with an increased incidence of co-morbidities, including detrusor underactivity (DU). DU is defined as the failure to create sufficient and durable expulsive force to adequately empty the urinary bladder during a normal voiding timespan. DU is prevalent in older adults, as evidenced by its prevalence in nearly two-thirds of nursing home residents. Current treatments are mostly palliative or come with many side effects. β-adrenoceptor-mediated relaxation is the primary mechanism of detrusor relaxation, and Hyperpolarization-activated Cyclic Nucleotide-gated (HCN) channels have previously been identified by us and others as a very important mediator of this relaxation, however the role of HCN in detrusor relaxation has not been elucidated. Hence, we seek to characterize its role in adrenergic relaxation mechanisms and spontaneous myocyte activity. Male and female 10–12-month-old C57Bl/6 mice were used for this study. Pharmacomyography studies were performed to assess the effect of different drugs that act at various steps along the adrenergic relaxation pathway, +/- CsCl, an HCN blockade at [5mM]. As expected, we saw that increasing HCN opening probability by isoproterenol or forskolin (adenylyl cyclase/cAMP-agonist) or lamotrigine (HCN-activator) resulted in decreases in tonic tension, but were diminished in the presence of CsCl. Mechanisms modulated by H89 (PKA-inhibitor) and NS1619 (BK-channel-agonist) show no change in tonic tension, however spontaneous phasic activity significantly increases. These data support increased cAMP, not hyperpolarization, as the key inductor of HCN in adrenergic relaxation.
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Szegedi, Viktor, Emőke Bakos, Szabina Furdan, Bálint H. Kovács, Dániel Varga, Miklós Erdélyi, Pál Barzó, Attila Szücs, Gábor Tamás, and Karri Lamsa. "HCN channels at the cell soma ensure the rapid electrical reactivity of fast-spiking interneurons in human neocortex." PLOS Biology 21, no. 2 (February 6, 2023): e3002001. http://dx.doi.org/10.1371/journal.pbio.3002001.
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Accumulating evidence indicates that there are substantial species differences in the properties of mammalian neurons, yet theories on circuit activity and information processing in the human brain are based heavily on results obtained from rodents and other experimental animals. This knowledge gap may be particularly important for understanding the neocortex, the brain area responsible for the most complex neuronal operations and showing the greatest evolutionary divergence. Here, we examined differences in the electrophysiological properties of human and mouse fast-spiking GABAergic basket cells, among the most abundant inhibitory interneurons in cortex. Analyses of membrane potential responses to current input, pharmacologically isolated somatic leak currents, isolated soma outside-out patch recordings, and immunohistochemical staining revealed that human neocortical basket cells abundantly express hyperpolarization-activated cyclic nucleotide-gated cation (HCN) channel isoforms HCN1 and HCN2 at the cell soma membrane, whereas these channels are sparse at the rodent basket cell soma membrane. Antagonist experiments showed that HCN channels in human neurons contribute to the resting membrane potential and cell excitability at the cell soma, accelerate somatic membrane potential kinetics, and shorten the lag between excitatory postsynaptic potentials and action potential generation. These effects are important because the soma of human fast-spiking neurons without HCN channels exhibit low persistent ion leak and slow membrane potential kinetics, compared with mouse fast-spiking neurons. HCN channels speed up human cell membrane potential kinetics and help attain an input–output rate close to that of rodent cells. Computational modeling demonstrated that HCN channel activity at the human fast-spiking cell soma membrane is sufficient to accelerate the input–output function as observed in cell recordings. Thus, human and mouse fast-spiking neurons exhibit functionally significant differences in ion channel composition at the cell soma membrane to set the speed and fidelity of their input–output function. These HCN channels ensure fast electrical reactivity of fast-spiking cells in human neocortex.
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Lee, Seul-Yi, Tuan Anh Vuong, Hyun-Kyung So, Hyun-Ji Kim, Yoo Bin Kim, Jong-Sun Kang, Ilmin Kwon, and Hana Cho. "PRMT7 deficiency causes dysregulation of the HCN channels in the CA1 pyramidal cells and impairment of social behaviors." Experimental & Molecular Medicine 52, no. 4 (April 2020): 604–14. http://dx.doi.org/10.1038/s12276-020-0417-x.
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Abstract HCN channels regulate excitability and rhythmicity in the hippocampal CA1 pyramidal cells. Perturbation in the HCN channel current (Ih) is associated with neuropsychiatric disorders, such as autism spectrum disorders. Recently, protein arginine methyltransferase 7 (PRMT7) was shown to be highly expressed in the hippocampus, including the CA1 region. However, the physiological function of PRMT7 in the CA1 neurons and the relationship to psychiatric disorders are unclear. Here we showed that PRMT7 knockout (KO) mice exhibit hyperactivity and deficits in social interaction. The firing frequency of the CA1 neurons in the PRMT7 KO mice was significantly higher than that in the wild-type (WT) mice. Compared with the WT CA1 neurons, the PRMT7 KO CA1 neurons showed a more hyperpolarized resting potential and a higher input resistance, which were occluded by the Ih-current inhibitor ZD7288; these findings were consistent with the decreased Ih and suggested the contribution of Ih-channel dysfunction to the PRMT7 KO phenotypes. The HCN1 protein level was decreased in the CA1 region of the PRMT7 KO mice in conjunction with a decrease in the expression of Shank3, which encodes a core scaffolding protein for HCN channel proteins. A brief application of the PRMT7 inhibitor DS437 did not reproduce the phenotype of the PRMT7 KO neurons, further indicating that PRMT7 regulates Ih by controlling the channel number rather than the open probability. Moreover, shRNA-mediated PRMT7 suppression reduced both the mRNA and protein levels of SHANK3, implying that PRMT7 deficiency might be responsible for the decrease in the HCN protein levels by altering Shank3 expression. These findings reveal a key role for PRMT7 in the regulation of HCN channel density in the CA1 pyramidal cells that may be amenable to pharmacological intervention for neuropsychiatric disorders.
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Kretschmannova, Karla, Marek Kucka, Arturo E. Gonzalez-Iglesias, and Stanko S. Stojilkovic. "The Expression and Role of Hyperpolarization-Activated and Cyclic Nucleotide-Gated Channels in Endocrine Anterior Pituitary Cells." Molecular Endocrinology 26, no. 1 (January 1, 2012): 153–64. http://dx.doi.org/10.1210/me.2011-1207.
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Abstract Pituitary cells fire action potentials independently of external stimuli, and such spontaneous electrical activity is modulated by a large variety of hypothalamic and intrapituitary agonists. Here, we focused on the potential role of hyperpolarization-activated and cyclic nucleotide-gated (HCN) channels in electrical activity of cultured rat anterior pituitary cells. Quantitative RT-PCR analysis showed higher level of expression of mRNA transcripts for HCN2 and HCN3 subunits and lower expression of HCN1 and HCN4 subunits in these cells. Western immunoblot analysis of lysates from normal and GH3 immortalized pituitary cells showed bands with appropriate molecular weights for HCN2, HCN3, and HCN4. Electrophysiological experiments showed the presence of a slowly developing hyperpolarization-activated inward current, which was blocked by Cs+ and ZD7288, in gonadotrophs, thyrotrophs, somatotrophs, and a fraction of lactotrophs, as well as in other unidentified pituitary cell types. Stimulation of adenylyl cyclase and addition of 8-Br-cAMP enhanced this current and depolarized the cell membrane, whereas 8-Br-cGMP did not alter the current and hyperpolarized the cell membrane. Both inhibition of basal adenylyl cyclase activity and stimulation of phospholipase C signaling pathway inhibited this current. Inhibition of HCN channels affected the frequency of firing but did not abolish spontaneous electrical activity. These experiments indicate that cAMP and cGMP have opposite effects on the excitability of endocrine pituitary cells, that basal cAMP production in cultured cells is sufficient to integrate the majority of HCN channels in electrical activity, and that depletion of phosphatidylinositol 4,5-bisphosphate caused by activation of phospholipase C silences them.
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Zhong, Ning, Vahri Beaumont, and Robert S. Zucker. "Calcium Influx Through HCN Channels Does Not Contribute to cAMP-Enhanced Transmission." Journal of Neurophysiology 92, no. 1 (July 2004): 644–47. http://dx.doi.org/10.1152/jn.00112.2004.
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Serotonin is a native neuromodulator of synaptic transmission at glutamatergic neuromuscular junctions of crayfish limb muscles. During times of stress, serotonin binds to presynaptic receptors, which activate adenylyl cyclase to elevate presynaptic levels of cAMP. cAMP binds to two presynaptic target proteins, hyperpolarization and cyclic nucleotide-activated (HCN) ion channels and an exchange protein activated by cAMP (Epac), and activation of these effectors results in enhancement of transmitter release to action potentials. cAMP elevation also results in a small preterminal rise in [Ca2+]i, which we show here to result from Ca2+ influx through the presynaptic HCN channels opened by cAMP. Little or no Ca2+ influx occurs through voltage-dependent Ca2+ channels, despite the small presynaptic depolarization caused by current through the HCN channels. Loading terminals with BAPTA delays the rise in preterminal [Ca2+]i without affecting the enhancement of transmission to cAMP elevation. This dissociation of the dynamics of the [Ca2+]i rise and synaptic enhancement, plus the small magnitude and location of [Ca2+]i elevation distant from release sites, seems to preclude any direct role for this [Ca2+]i elevation in cAMP-dependent enhancement of transmission.
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Yang, Zhen, and Fidel Santamaria. "Purkinje cell intrinsic excitability increases after synaptic long term depression." Journal of Neurophysiology 116, no. 3 (September 1, 2016): 1208–17. http://dx.doi.org/10.1152/jn.00369.2016.
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Coding in cerebellar Purkinje cells not only depends on synaptic plasticity but also on their intrinsic membrane excitability. We performed whole cell patch-clamp recordings of Purkinje cells in sagittal cerebellar slices in mice. We found that inducing long-term depression (LTD) in the parallel fiber to Purkinje cell synapses results in an increase in the gain of the firing rate response. This increase in excitability is accompanied by an increase in the input resistance and a decrease in the amplitude of the hyperpolarization-activated cyclic nucleotide-gated (HCN) channel-mediated voltage sag. Application of a HCN channel blocker prevents the increase in input resistance and excitability without blocking the expression of synaptic LTD. We conclude that the induction of parallel fiber-Purkinje cell LTD is accompanied by an increase in excitability of Purkinje cells through downregulation of the HCN-mediated h current. We suggest that HCN downregulation is linked to the biochemical pathway that sustains synaptic LTD. Given the diversity of information carried by the parallel fiber system, we suggest that changes in intrinsic excitability enhance the coding capacity of the Purkinje cell to specific input sources.
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Bolívar, Juan J., Dagoberto Tapia, Gabina Arenas, Mauricio Castañón-Arreola, Haydee Torres, and Elvira Galarraga. "A hyperpolarization-activated, cyclic nucleotide-gated, (Ih-like) cationic current and HCN gene expression in renal inner medullary collecting duct cells." American Journal of Physiology-Cell Physiology 294, no. 4 (April 2008): C893—C906. http://dx.doi.org/10.1152/ajpcell.00616.2006.
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The cation conductancein primary cultures of rat renal inner medullary collecting duct was studied using perforated-patch and conventional whole cell clamp techniques. Hyperpolarizations beyond −60 mV induced a time-dependent inward nonselective cationic current ( Ivti) that resembles the well-known hyperpolarization-activated, cyclic nucleotide-gated Ih and If currents. Ivti showed a half-maximal activation around −102 mV with a slope factor of 25 mV. It had a higher conductance (but, at its reversal potential, not a higher permeability) for K+ than for Na+ ( gK+/ gNa+ = 1.5), was modulated by cAMP and blocked by external Cd2+ (but not Cs+ or ZD-7288), and potentiated by a high extracellular K+ concentration. We explored the expression of the Ih channel genes (HCN1 to -4) by RT-PCR. The presence of transcripts corresponding to the HCN1, -2, and -4 genes was observed in both the cultured cells and kidney inner medulla. Western blot analysis with HCN2 antibody showed labeling of ∼90- and ∼120-kDa proteins in samples from inner medulla and cultured cells. Immunocytochemical analysis of cell cultures and inner medulla showed the presence of HCN immunoreactivity partially colocalized with the Na+-K+-ATPase at the basolateral membrane of collecting duct cells. This is the first evidence of an Ih-like cationic current and HCN immunoreactivity in either kidney or any other nonexcitable mammalian cells.
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Luo, Zuyun, Fangfang Wang, Jinjia Xu, Jieying Liu, and Ruoyu Hong. "Thermodynamic Simulation and Experimental Investigation of Plasma Preparation of Nanosized Carbon Using Propane." Journal of Nanomaterials 2019 (April 17, 2019): 1–13. http://dx.doi.org/10.1155/2019/9189525.
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Carbon black was prepared by pyrolysis of propane under different plasma conditions. The effects of the flow ratio of the carbon precursor, discharge current, and plasma gases (including argon, nitrogen, and hydrogen) on the morphology and structure of carbon black were investigated by a series of physical characterizations. The equilibrium components were computed based on the minimization of the Gibbs free energy. The theoretical analysis and experimental results confirmed that HCN is the inevitable byproduct in the tail gas from the nitrogen plasma process, indicating that nitrogen is inappropriate as the carrier gas for the preparation of carbon black. The effects of discharging current, discharging spacing, and proportions of propane were also symmetrically studied by the evaluation of HCN concentration. Moreover, the graphene was generated when using argon as the plasma gas mixed with a small amount of hydrogen.
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Liu, Chang, Changan Xie, Khade Grant, Zhuocheng Su, Weihua Gao, Qinglian Liu, and Lei Zhou. "Patch-clamp fluorometry–based channel counting to determine HCN channel conductance." Journal of General Physiology 148, no. 1 (June 27, 2016): 65–76. http://dx.doi.org/10.1085/jgp.201511559.
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Counting ion channels on cell membranes is of fundamental importance for the study of channel biophysics. Channel counting has thus far been tackled by classical approaches, such as radioactive labeling of ion channels with blockers, gating current measurements, and nonstationary noise analysis. Here, we develop a counting method based on patch-clamp fluorometry (PCF), which enables simultaneous electrical and optical recordings, and apply it to EGFP-tagged, hyperpolarization-activated and cyclic nucleotide–regulated (HCN) channels. We use a well-characterized and homologous cyclic nucleotide–gated (CNG) channel to establish the relationship between macroscopic fluorescence intensity and the total number of channels. Subsequently, based on our estimate of the total number of HCN channels, we determine the single-channel conductance of HCN1 and HCN2 to be 0.46 and 1.71 pS, respectively. Such a small conductance would present a technical challenge for traditional electrophysiology. This PCF-based technique provides an alternative method for counting particles on cell membranes, which could be applied to biophysical studies of other membrane proteins.
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Porro, Alessandro, Cristiano Bolchi, Federico Brandalise, Rebecca Appiani, Roberta Leone, Federico Thei, Gerhard Thiel, Marco Pallavicini, and Anna Moroni. "Design of a photo-activatable ivabradine to enable light induced block of HCN current in tissues." Biophysical Journal 122, no. 3 (February 2023): 390a. http://dx.doi.org/10.1016/j.bpj.2022.11.2131.
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Scharfman, Helen E. "Keeping Pace with Pacemaker Channels." Epilepsy Currents 2, no. 5 (September 2002): 155–56. http://dx.doi.org/10.1111/j.1535-7597.2002.00058.x.
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Developmental Febrile Seizures Modulate Hippocampal Gene Expression of Hyperpolarization-activated Channels in an Isoform and Cell-specific Manner Brewter A, Bender RA, Chen Y, Dube C, Eghbal-Ahmadi M, and Baram TZ J Neurosci 2002;22:4591–4599 Febrile seizures, in addition to being the most common seizure type of the developing human, may contribute to the generation of subsequent limbic epilepsy. Our previous work demonstrated that prolonged experimental febrile seizures in the immature rat model increased hippocampal excitability in the long term, enhancing susceptibility to future seizures. The mechanisms for these profound proepileptogenic changes did not require cell death and were associated with long-term slowed kinetics of the hyperpolarization activated depolarizing current (Ih). Here we show that these seizures modulate the expression of genes encoding this current, the hyperpolarization-activated, cyclic nucleotide–gated channels (HCNs): In CA1 neurons expressing multiple HCN isoforms, the seizures induced a coordinated reduction of HCN1 mRNA and enhancement of HCN2 expression, thus altering the neuronal HCN phenotype. The seizure-induced augmentation of HCN2 expression involved CA3 in addition to CA1, whereas for HCN4, mRNA expression was not changed by the seizures in either hippocampal region. This isoform- and region-specific transcriptional regulation of HCNs required neuronal activity rather than hyperthermia alone, correlated with seizure duration, and favored the formation of slow-kinetics HCN2-encoded channels. In summary, these data demonstrate a novel, activity-dependent transcriptional regulation of HCN molecules by developmental seizures. These changes result in long-lasting alteration of the HCN phenotype of specific hippocampal neuronal populations, with profound consequences on the excitability of the hippocampal network.
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Chen, Xiangdong, Shaofang Shu, and Douglas A. Bayliss. "Suppression of Ih Contributes to Propofol-Induced Inhibition of Mouse Cortical Pyramidal Neurons." Journal of Neurophysiology 94, no. 6 (December 2005): 3872–83. http://dx.doi.org/10.1152/jn.00389.2005.
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The contributions of the hyperpolarization-activated current, Ih, to generation of rhythmic activities are well described for various central neurons, particularly in thalamocortical circuits. In the present study, we investigated effects of a general anesthetic, propofol, on native Ih in neurons of thalamus and cortex and on the corresponding cloned HCN channel subunits. Whole cell voltage-clamp recordings from mouse brain slices identified neuronal Ih currents with fast activation kinetics in neocortical pyramidal neurons and with slower kinetics in thalamocortical relay cells. Propofol inhibited the fast-activating Ih in cortical neurons at a clinically relevant concentration (5 μM); inhibition of Ih involved a hyperpolarizing shift in half-activation voltage (Δ V1/2 approximately −9 mV) and a decrease in maximal available current (∼36% inhibition, measured at −120 mV). With the slower form of Ih expressed in thalamocortical neurons, propofol had no effect on current activation or amplitude. In heterologous expression systems, 5 μM propofol caused a large shift in V1/2 and decrease in current amplitude in homomeric HCN1 and linked heteromeric HCN1–HCN2 channels, both of which activate with fast kinetics but did not affect V1/2 or current amplitude of slowly activating homomeric HCN2 channels. With GABAA and glycine receptor channels blocked, propofol caused membrane hyperpolarization and suppressed action potential discharge in cortical neurons; these effects were occluded by the Ih blocker, ZD-7288. In summary, these data indicate that propofol selectively inhibits HCN channels containing HCN1 subunits, such as those that mediate Ih in cortical pyramidal neurons—and they suggest that anesthetic actions of propofol may involve inhibition of cortical neurons and perhaps other HCN1-expressing cells.
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Wechselberger, Martin, Chadwick L. Wright, Georgia A. Bishop, and Jack A. Boulant. "Ionic channels and conductance-based models for hypothalamic neuronal thermosensitivity." American Journal of Physiology-Regulatory, Integrative and Comparative Physiology 291, no. 3 (September 2006): R518—R529. http://dx.doi.org/10.1152/ajpregu.00039.2006.
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Thermoregulatory responses are partially controlled by the preoptic area and anterior hypothalamus (PO/AH), which contains a mixed population of temperature-sensitive and insensitive neurons. Immunohistochemical procedures identified the extent of various ionic channels in rat PO/AH neurons. These included pacemaker current channels [i.e., hyperpolarization-activated cyclic nucleotide-gated channels (HCN)], background potassium leak channels (TASK-1 and TRAAK), and transient receptor potential channel (TRP) TRPV4. PO/AH neurons showed dense TASK-1 and HCN-2 immunoreactivity and moderate TRAAK and HCN-4 immunoreactivity. In contrast, the neuronal cell bodies did not label for TRPV4, but instead, punctate labeling was observed in traversing axons or their terminal endings. On the basis of these results and previous electrophysiological studies, Hodgkin–Huxley-like models were constructed. These models suggest that most PO/AH neurons have the same types of ionic channels, but different levels of channel expression can explain the inherent properties of the various types of temperature-sensitive and insensitive neurons.
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Long, Feng, Arthur D. Bosman, Paolo Cazzoletti, Ewine F. van Dishoeck, Karin I. Öberg, Stefano Facchini, Marco Tazzari, Viviana V. Guzmán, and Leonardo Testi. "Exploring HNC and HCN line emission as probes of the protoplanetary disk temperature." Astronomy & Astrophysics 647 (March 2021): A118. http://dx.doi.org/10.1051/0004-6361/202039336.
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Context. The distributions and abundances of molecules in protoplanetary disks are powerful tracers of the physical and chemical disk structures. The abundance ratios of HCN and its isomer HNC are known to be sensitive to gas temperature. Their line ratios might therefore offer a unique opportunity to probe the properties of the emitting gas. Aims. We investigate the HNC and HCN line emission in disks at (sub-)millimeter wavelengths and explore their potential utility for probing disk temperature and other disk properties. Methods. Using the 2D thermochemical code DALI, we ran a set of disk models accounting for different stellar properties and radial and vertical disk structures, with an updated chemical network for the nitrogen chemistry. These modeling results were then compared with observations, including new observations obtained with the Atacama Large Millimeter/submillimeter Array (ALMA) of HNC J = 3−2 for the TW Hya disk and HNC J = 1−0 for 29 disks in Lupus. Results. Similar to CN, HCN and HNC have brighter line emission in models with larger disk flaring angles and higher UV fluxes. HNC and HCN are predicted to be abundant in the warm surface layer and outer midplane region, which results in ring-shaped emission patterns. However, the precise emitting regions and emission morphology depend on the probed transition, as well as on other parameters such as C and O abundances. The modeled HNC-to-HCN line intensity ratio increases from <0.1 in the inner disk to up to 0.8 in the outer disk regions, which can be explained by efficient HNC destruction at high temperatures. Disk-integrated HNC line fluxes from current scarce observations and its radial distribution in the TW Hya disk are broadly consistent with our model predictions. Conclusions. The HNC-to-HCN flux ratio robustly increases with radius (decreasing temperature), but its use as a chemical thermometer in disks is affected by other factors, including UV flux and C and O abundances. High-spatial resolution ALMA disk observations of HNC and HCN that can locate the emitting layers would have the great potential to constrain both the disk thermal and UV radiation structures, and also to verify our understanding of the nitrogen chemistry.