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Ion Channels of Reward Pathway in Drug Abuse
Published in Tian-Le Xu, Long-Jun Wu, Nonclassical Ion Channels in the Nervous System, 2021
HCNs are voltage-gated cation channels that are activated with hyperpolarization. They open at membrane potentials more negative than −50 mV, thus they are active at the resting membrane potential of neurons. These channels are permeable to both Na+ and K+, resulting in a depolarizing current at rest, which inevitably also influences the membrane resistance. The current mediated by HCNs is also called Ih current; Ih has significant influences on neuron activity. For example, Ih plays an important role in the tonic firing of Purkinje cells in the cerebellum (Williams et al. 2002). As Ih decreases membrane resistance, its activity limits low threshold Ca2+ channel activity and both the amplitude and kinetics of EPSP in dendrites. These effects lead to the decrease of EPSP summation and dendritic excitability in neurons (Tsay, Dudman, and Siegelbaum 2007; Shah et al. 2004; Magee 1998). The HCN family contains four subunits, HCN1–4. The HCN1 subunit is expressed in the cortex, hippocampus, cerebellum, and brain stem. The HCN2 subunit is expressed in high abundance in the thalamus and brain stem. HCN3 is expressed relatively low in the CNS, and HCN4 is expressed specifically to the olfactory bulb (Moosmang et al. 1999).
Restoration of Membrane Environments for Membrane Proteins for Structural and Functional Studies
Published in Qiu-Xing Jiang, New Techniques for Studying Biomembranes, 2020
As shown in Section 3.1, a negative transmembrane potential can be established with the desired magnitude. It would be ideal if all the reconstituted HCN2 channels were inserted outside-out. However, only about 20% of the reconstituted membrane proteins are inserted outside-out (the rest are inserted inside-out) [19]. To open the majority of HCN2 channels (the inside-out inserted channels), the potential inside liposomes needs to be positive with respect to the external solution. As shown in Figure 8.4a, a positive transmembrane potential can be established. However, this positive transmembrane potential cannot be assessed using the flux assay method discussed in Section 3.1. Here, cryo-EM method was employed. The potential associated with a liposome made of neutral lipids consists of a dipole potential and a transmembrane potential (Figure 8.4b). The corresponding membrane scattering profile is asymmetric as shown in Figure 8.4c.
Mechanisms of action of vitamin B1 (thiamine), B6 (pyridoxine), and B12 (cobalamin) in pain: a narrative review
Published in Nutritional Neuroscience, 2023
A. M. Paez-Hurtado, C. A. Calderon-Ospina, M. O. Nava-Mesa
In a chronic compression of the DRG model in rats, inhibition of spontaneous ectopic discharges of dorsal root fibers associated with cyanocobalamin were also reported [11,108,109]. Ectopic discharges in primary afferent neurons play an essential role in the development of neuropathic pain. It is suggested that axons with injured terminal arbors may lead to abnormal spontaneous discharges. The possible inhibitory action of vitamin B12 on NADPH oxidase activation and the downstream regulation of NFκB pathway may contribute to the modulation of anti-inflammatory and pro-inflammatory cytokines in the spinal DRG [14]. The potentiation of the antiallodynic and analgesic effect of peripheral pain signals may also be related to the inhibition of hyperpolarization of activated cationic currents and hyperexcitability of injured DGR neurons [97,108]. The possible modulation of HCN1 and HCN2 channels of DRG may result in a pain-relieving effect of this vitamin [11].
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
We choose a strategy based on the use of a siRNA against the rat HCN2 mRNA to selectively knockdown the expression of the HCN2 ion channel. We tested four different sequences of siRNA (A-D) but only two of these sequences (B and C) achieved a complete in vitro knockdown of HCN2 expression (Figure 1). siRNAs are custom-designed double-stranded RNA sequences that load into the RNA-induced silencing complex (RISC) and target mRNA for cleavage and degradation, resulting in the prevention of protein translation. The differences in knockdown efficiency observed among the tested siRNA sequences could be explained by the formation of secondary structures in the target mRNA that impairs the access and interaction of the RISC complex with its target mRNA region (26,27).
Role of ivabradine and heart rate lowering in chronic heart failure: guideline update
Published in Expert Review of Cardiovascular Therapy, 2018
Sheryl L Chow, Robert L. Page, Christophe Depre
No meaningful increases in ventricular arrhythmias were observed in the three largest randomized clinical trials testing ivabradine [13,60,81]. HF is a risk factor for ventricular arrhythmias [82] and recent evidence suggests a potential role for increased HCN2 and HCN4 channel density as an underlying mechanism of ventricular arrhythmias [83]. Preclinical experiments with ivabradine treatment led to reduced lethal ventricular arrhythmias in a mouse model of dilated cardiomyopathy.