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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).
Pharmacology of the lower urinary tract
Published in Jacques Corcos, David Ginsberg, Gilles Karsenty, Textbook of the Neurogenic Bladder, 2015
Several observations indicate that laminia propria ICs could be involved in the coordination of local bladder signaling processes. Mukerji et al.131 reported muscarinic (M2 and M3) receptors immunoreactivity on cells in the LP resembling IC, a finding confirmed by Grol et al.132 Mukerji et al.131 suggested that these cells could respond to cholinergic signaling. However, Sui et al.133 reported that suburothelial IC did not respond to carbachol but application of ATP elicited Ca2+ transients. P2Y6 receptors may mediate these excitatory responses.134 Further studies on spinal cord injured (SCI) rats, where laminia propria ICs are upregulated, suggested that this effect of ATP and other P2Y agonists could increase spontaneous contractile activity in the bladder.134 Xue et al.135 demonstrated that vimentin+ (and some KIT+) laminia propria ICs in the human bladder expressed hyperpolarization-activated cyclic nucleotide-gated (HCN) channels, particularly HCN4. This channel is specialized for the If current, which is a characteristic of pacemaker cells, and it was suggested that HCN4 could be involved in the generation of spontaneous bladder activity during filling. However, further functional studies are needed to put these data into proper perspective.
Risks of cardiovascular toxicities associated with ALK tyrosine kinase inhibitors in patients with non-small-cell lung cancer: a meta-analysis of randomized control trials
Published in Expert Opinion on Drug Safety, 2023
Jin Zhao, Zhuo Ma, Hao Li, Dan Sun, Yi Hu, Chen Zhang, Yuhui Zhang
There are also some reports on the mechanisms leading to the high risk of cardiac disorders associated with ALK-TKIs. Zhushan et al. found that crizotinib’s effects on hyperpolarization-activated cyclic nucleotide-gated channel 4 (HCN4) channels can lead to bradycardia [42]. Besides, crizotinib was considered causing QT prolongation by inhibiting the ion channel responsible for the delayed-rectifier K+ current in the heart (IKr) [43]. Kimberly et al. found that crizotinib may induce cardiomyocyte death by increasing the production of reactive oxygen species (ROS), activating caspase, accumulating cholesterol, interrupting the beating rate of cardiomyocytes, and blocking ion channels [44], which may further explain the cardiovascular toxicities of ALK-TKIs. However, there was no evidence of cardiac disorders in clinical trials to corroborate this theory, and research on the mechanisms of the vascular toxicities associated with ALK TKIs are also blank, the detailed pathogenic cardiovascular toxicities mechanism remains to be studied.
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
This study clearly confirms that HCC smooth muscle expresses HCN3 and HCN4 channels. In addition, ivabradine appears to be related to HCN3 and HCN4 channel inhibition in HCC. Our data indicate that expression and localization of HCN3 and HCN4 channels were not altered after incubation with ivabradine. A previous study revealed that HCN3 and HCN4 channels were expressed in the human ureter and were involved in the peristaltic contraction of isolated ureteral smooth muscle strips [58]. After incubation with, ZD7288, the specific blocker of HCN channels, this peristaltic activity was reduced [58]. In addition, HCN3 and HCN4 channel isoforms were observed in the rat bladder and similarly influenced bladder excitation [59]. HCN channel expression and function are also involved in spinal cord injury-induced neurogenic bladder and detrusor over-activity [59–61]. Hence, ivabradine may serve as a valid treatment for a variety of urogenital conditions.
Correlation between HCN4 gene polymorphisms and lone atrial fibrillation risk
Published in Artificial Cells, Nanomedicine, and Biotechnology, 2019
Xiao-Hong Li, Ya-Min Hu, Guang-Li Yin, Ping Wu
Hyperpolarization activated cyclic nucleotide gated potassium channel 4 (HCN4) is one subtype of HCN family. HCN family could code the funny current (If) pathway which is the necessary element for cardiac pacemaking process [14,15]. Besides, HCNs are also involved in the spontaneous membrane depolarization process of SA node cells during diastole [16]. Stieber et al. found that HCN4 was overexpressed in embryonic heart, especially in SA node [17]. Mutations in this gene have been proved to be associated with AF [18]. A meta-analysis based on multiple GWAS samples of European population identified that rs7164883 SNP of HCN4 gene was a susceptibility loci for AF [19]. Furthermore, the single nucleotide polymorphisms (SNPs) in HCN4 gene (rs498005 and rs7164883) were with the minor allele frequencies more than 0.05 in CHB (Chinese Han in Beijing) population. Thus, we hypothesize that the two SNPs might be associated with AF in Chinese Han population.