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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).
Histamine as Neurotransmitter
Published in Divya Vohora, The Third Histamine Receptor, 2008
Oliver Selbach, Helmut L. Haas
Histaminergic neurons resemble the other aminergic neuron populations in many respects. They fire slowly at 1–4 Hz in the absence of synaptic activation [71,72], even in isolated neurons [73]. In behaving animals (cats, rats, and mice), the firing pattern is variable during waking, depending on the arousal state, and missing during sleep [60,74–76] (Figure 3.4) (for review, see Ref. 77). Recordings from identified TMN neurons revealed a membrane potential of about –50 mV and a broad action potential (up to 2 ms midamplitude duration at 35°C) with a significant contribution from Ca2+ channels followed by a deep (15–20 mV) afterhyperpolarization. Two opposing membrane conductances give the TMN neurons a typical electrophysiological appearance (Figure 3.2). The response to a hyperpolarizing current injection deviates from a capacitive behavior through activation of a depolarizing current of the h-type [78]. HCN3 and HCN1 are predominantly found in the rat; the current is not modified by cyclic nucleotides. The involvement of Ih in the TMN pacemaker cycle is questionable as blocking Ih through Cs ions does not affect the firing rate, and the half maximal activation occurs at about –100 mV [79,80], whereas the afterhyperpolarization takes the membrane potential from –75 to –80 mV [81]. This afterhyperpolarization is sufficient to remove inactivation of the fast outward current (IAfast, 4-aminopyridine sensitive) [82] that delays the return to firing threshold and thus slows the firing. A further inactivating K-current (IAslow), which is not blocked by 4-aminopyridine and requires long-lasting hyperpolarizations for removal of inactivation, is unlikely to affect spontaneous firing. A recent detailed analysis of the A-type current in mouse TMN revealed a subthreshold activation of IA by fast ramps that imitated the spontaneous depolarizations during pacemaking [83].
Cannabis alters DNA methylation at maternally imprinted and autism candidate genes in spermatogenic cells
Published in Systems Biology in Reproductive Medicine, 2022
Rose Schrott, Katherine W. Greeson, Dillon King, Krista M. Symosko Crow, Charles A. Easley, Susan K. Murphy
HCN1 encodes hyperpolarization-activated cyclic nucleotide-gated voltage-gated ion channels that play a role in regulating neurotransmission and influencing synaptic plasticity in cortical neurons (Huang et al. 2011; Huang et al. 2017; Yang et al. 2018). HCN1 has important roles in controlling dendritic functional integration in hippocampal development and contributing to adult hippocampal function (Seo et al. 2015; Yang et al. 2018). Knockout of Hcn1 in mice results in impaired motor learning and memory and has been associated with drug-induced cognitive dysfunction (Seo et al. 2015; Yang et al. 2018). Importantly, mutations in HCN1 are associated with a range of epileptic phenotypes (Seo et al. 2015; Marini et al. 2018). Interestingly, autism spectrum disorders are associated with epilepsy, with many individuals with autism developing seizure disorders later in life (Tuchman and Cuccaro 2011). Thus, while its role in neurodevelopmental disorders is still being elucidated, possible comorbidities should be considered. It is also known that HCN1 plays an important role in controlling brain development and in regulating the excitability of neurons (Yang et al. 2018). Thus, alterations in how this gene is expressed, including epigenetic changes that influence gene expression, could have profound consequences for neurodevelopment, if the HCN1 methylation changes in sperm are heritable.
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
HCN belongs to voltage-gated cation channel family, including four subunits (HCN1-4). In the atrial tissues, HCN4 is the main subunit. Voltage dependence and the permeability of K+ and Na+ are the mainly electrophysiological properties of HCN channel. In addition, HCN4 could regulate the funny current. Thus, we considered that the polymorphisms in HCN4 gene might affect the atrial potential, thus influencing the occurrence of AF. We selected two SNPs which were with the minor allele frequencies (MAF) more than 0.05 in the intron region of HCN4 gene to explore the association of HCN4 SNPs with lone AF risk and ALP of the patients.
Investigational new drugs for the treatment of Dravet syndrome: an update
Published in Expert Opinion on Investigational Drugs, 2023
Slobodan M. Janković, Snežana V. Janković, Radiša Vojinović, Snežana Lukić
Dravet syndrome is a form of severe myoclonic epilepsy in infants, which was discovered as a separate clinical entity by the French neurologist Charlotte Dravet in 1978 [1], after whom the syndrome was named a little later (in 1989). The diagnosis of Dravet syndrome is clinical, and before genetic testing became widely available it was in some occasions made late, because it takes time for all symptoms and signs to manifest: seizures beginning in the first year of life in a previously completely healthy child, secondary occurrence of myoclonic seizures, family history of epilepsy or febrile seizures, generalized spike-wave (SW) and polyspike-wave (PolySW) observed in EEG, photosensitivity, neurological signs accompanying epilepsy (ataxia, pyramidal signs, myoclonus between seizures), cognitive deterioration from the second year of life with slowed psychomotor development, personality disorders later in childhood and resistance to usual anticonvulsant therapy [2]. The basis of the disease is a disturbed function of sodium ion channels in neuron membranes, which in about 80% of the children is caused by some kind of mutation on the alpha subunit of the SCN1A gene. However, the problem with this syndrome is its clinical and genetic heterogeneity, because in addition to the typical clinical form, there are others (lack of myoclonic seizures, absence of neurological signs, almost normal psychomotor development in the first 4 years of life), and in addition to several types of abnormalities of the SCN1A gene, mutations of other genes (PCDH19, SCN1B, GABRG2, HCN1, GABRA1, HCN1, and STXBP1) can also lead to other types of Dravet syndrome; finally, there are patients without proven genetic mutations, and people with the mentioned mutations, but without the syndrome [3,4].