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Nonclassical Ion Channels in Depression
Published in Tian-Le Xu, Long-Jun Wu, Nonclassical Ion Channels in the Nervous System, 2021
The HCN channel is primarily expressed in the brain, heart, and retina3, and modulates neuronal excitability and activity through a hyperpolarization-activated current (Ih) consisting of Na+ and K+ cations4,5. HCN channels are voltage-gated and modulated by the endogenous ligand cyclic adenosine 3’,5’-monophosphate (cAMP), the opening of which (typically at potentials below −50 mV) causes membrane depolarization and decreases membrane resistance. Neuronal network activity can be affected by HCN expression levels, its localization to subcellular compartments, and the composition of its subunits6. Given the role of Ih and HCN channels in controlling synaptic transmission and rhythmic oscillatory activity in the brain7, disruption of HCN channel function can be involved in the development of depression or targeted as a therapeutic strategy.
Neurons
Published in Nassir H. Sabah, Neuromuscular Fundamentals, 2020
HCN channels are partially activated at rest, conducting an inward predominantly Na+ current that slightly depolarizes the resting membrane voltage. The resting membrane voltage is stabilized by the HCN channels, since a small hyperpolarization activates these channels whose inward current then depolarizes the cell. Similarly, a small depolarization deactivates the HCN channels, which hyperpolarizes the membrane back to the resting voltage.
Cardiovascular physiology
Published in Peter Kam, Ian Power, Michael J. Cousins, Philip J. Siddal, Principles of Physiology for the Anaesthetist, 2015
Peter Kam, Ian Power, Michael J. Cousins, Philip J. Siddal
The maximum diastolic potential of a sinus node cell is −65 mV. Phases 1 and 2 (of the fast response cardiac action potential) are absent in the SA node as there is no depolarization plateau (Figure 4.4). Phase 4. The pacemaker current is determined by ‘hyperpolarization-activated cyclic nucleotide’-gated (HCN) channels. From the maximum diastolic potential (–65 mV), a slow spontaneous depolarization slowly towards a threshold potential f approximately −40 mV. The pacemaker potential is produced by a fall in potassium permeability (iK) and an inward sodium ‘funny’ current (If) produced by the opening of sodium channels. The funny current is a mixed sodium–potassium current that is activated when the SA action potential is repolarized below about −40 to −50 mV and provides the inward current that is responsible for initiating the diastolic depolarization phase. The funny current is also activated by cyclic AMP. The binding of cyclic AMP to the If channels enhances the opening of the channels. Sympathetic stimulation increases cyclic AMP molecules, which bind to the If channels and increase the diastolic current resulting in an increase in the steepness of the diastolic depolarization phase. Ivabridine is a selective If inhibitor used to control tachycardia that is resistant to conventional anti-arrhythmic drugs. The slow inward current brings the membrane to the threshold potential (–40 mV) of T-type calcium channels, which open for the upstroke. The voltage-gated increase in calcium permeability via transient calcium channels result in an inward movement of calcium ions. The SA node exhibits automaticity as it spontaneously generates action potentials without neural input.Phase 0. Depolarization is produced by the opening of long-lasting (L-type) voltage-gated calcium channels (iCaL) and inward movement of positive ions. There is no sodium current involved in the SA node potential. The SA node potential reaches a peak at about 20 mV.Phase 3. Repolarization is accomplished by a late increase in potassium permeability and outward flow of ions. This is the result of an increase in repolarizing currents (iK becomes activated by positive potentials), causing a late increase in potassium permeability and outward flow of ions.
Gene knockdown of HCN2 ion channels in the ventral tegmental area reduces ethanol consumption in alcohol preferring rats
Published in The American Journal of Drug and Alcohol Abuse, 2022
Catalina Salinas-Luypaert, Felipe Sáez-Cortez, María Elena Quintanilla, Mario Herrera-Marschitz, Mario Rivera-Meza
Dopamine neurons are characterized by showing spontaneous activity, which is independent of their synaptic signaling (7). This pacemaker firing is maintained by an inward cation (Na+, K+) depolarizing current, which is activated by membrane hyperpolarization. This current (Ih) sets the membrane potential to further positive voltages, close to the activation threshold of calcium channels, resulting in a continuous firing of the neurons. The ion channels underlying the Ih current are known as hyperpolarization-activated cyclic nucleotide gated (HCN) ion channels (8,9). HCN channels, widely expressed in the brain and the heart, are encoded by four genes (HCN1-4) that share 60% of sequence homology. In the rat brain the four variants of HCN channels are expressed, but showing differences in their abundance and distribution. Particularly in the mesolimbic system, studies have shown that both the HCN1 and HCN2 isoforms are expressed in NAc, while HCN2 is the most abundant isoform in the VTA (10,11).
Ivabradine, the hyperpolarization-activated cyclic nucleotide-gated channel blocker, elicits relaxation of the human corpus cavernosum: a potential option for erectile dysfunction treatment
Published in The Aging Male, 2020
Serap Gur, Laith Alzweri, Didem Yilmaz-Oral, Ecem Kaya-Sezginer, Asim B. Abdel-Mageed, Suresh C. Sikka, Wayne J. G. Hellstrom
In in vitro studies, the relaxation response to EFS was enhanced approximately 2-fold by incubation with ivabradine. The contractile response to EFS in HCC strips was also reduced in the presence of ivabradine. It appears that alterations of relaxation and contraction to EFS after ivabradine are related to ion channel activity. Previous studies demonstrated that Ca2+-signaling pathways play an important role in cell dynamics involving electrical signaling/interactions of chemophysiology and electrophysiology [38,39]. HCN channels have important roles that control neuronal and cellular excitability and generate rhythmic oscillatory activity in both peripheral and central nervous systems [50–52]. In addition, the generation of HCN channel-null animals showed dysregulated neuronal activity [53]. HCN channels, potentially modulated by the NO/cGMP pathway, can influence neuronal excitability [54]. A study on rat optic nerve found that NO depolarized axons through cGMP acting on HCN channels [55]. In previous research, the excitatory effect of endogenous NO on gastroesophageal vagal afferents was inhibited by the HCN channel blocker ivabradine [56]. In contrast, the blockade of HCN channels increased the excitability of both the soma and peripheral vagal afferent mechanoreceptors (baroreceptors) in the aortic arch [57]. These discrepancies in the effect of HCN channels on neuron excitability may be due to the different subtypes of HCN channel involved.
Pharmacological management of atrial fibrillation in patients with heart failure with reduced ejection fraction: review of current knowledge and future directions
Published in Expert Review of Cardiovascular Therapy, 2020
One of the key clinical predicaments of AF and HFrEF is attempting to control the ventricular rate with poor functional reserve and oftentimes low blood pressure. This is particularly difficult as many of the rate slowing drugs such as beta-blockers and calcium channel blockers exhibit both negative chronotropic and inotropic effects. The ability to safely control the ventricular rate of patient’s in AF without a negative inotropic effect remains an unmet need, particularly in patients with decompensated heart failure. Ivabradine blocks HCN channels and thus effects in If current slowing the rate of depolarization in nodal cells. HCN channels are found predominantly in the sinoatrial node, but a number of mouse, rat, and human studies demonstrate their presence within the AV node as well [143–146]. Canine models suggest ivabradine has AV nodal-dependent slowing of HR in AF [147,148]. There are limited data on the effectiveness of ivabradine in humans with AF, but 2 initial studies have shown the ability of ivabradine to reduce the ventricular rate in patients with AF and that the addition of ivabradine to patient on beta-blockers further reduced HR without a corresponding decrease in BP [149,150]. For patients with HFrEF and SR, ivabradine treatment reduces the rate of cardiovascular hospitalizations without significant decreasing blood pressure [151]. Currently, the BRAKE AF trial (NCT03718273) is looking at ivabradine vs digoxin for patients with permanent AF and being treated with beta-blocker or Ca2+ channel antagonists.