Yoon-Sil Yang

Hypoxia typically accompanies acute inflammatory responses in patients and animal models. However, a limited number of studies have examined the effect of hypoxia in combination with inflammation (Hypo-Inf) on neural function. We previously reported that neuronal excitability in hippocampal CA1 neurons decreased during hypoxia and greatly rebounded upon reoxygenation. We attributed this altered excitability mainly to the dynamic regulation of hyperpolarization-activated cyclic nucleotide-gated cation (HCN) channels and input resistance. However, the molecular mechanisms underlying input resistance changes by Hypo-Inf and reperfusion remained unclear. In the present study, we found that a change in the density of the delayed rectifier potassium current (I_DR) can explain the input resistance variability. Furthermore, voltage-dependent inactivation of A-type potassium (I_A) channels shifted in the depolarizing direction during Hypo-Inf and reverted to normal upon reperfusion without a significant alteration in the maximum current density. Our results indicate that changes in the input resistance, and consequently excitability, caused by Hypo-Inf and reperfusion are at least partially regulated by the availability and voltage dependence of K_V channels. Moreover, these results suggest that selective K_V channel modulators can be used as potential neuroprotective drugs to minimize hypoxia- and reperfusion-induced neuronal damage.

Oxidative stress causes neuronal cell death in various neurodegenerative diseases, such as Alzheimer’s disease, ischemia, and Parkinson’s disease. Therefore, reducing intracellular reactive oxygen species (ROS) has been evaluated as an effective treatment strategy for neurodegenerative disorders. Methyl lucidone (MLC) extracted fromLindera erythrocarpaMakino (Lauraceae) has been previously reported to exhibit microglial-mediated neuroprotective effects via inhibiting neuroinflammation. However, the antioxidant effects of MLC are still unclear. The aim of this study was to determine the neuroprotective mechanism of MLC in HT-22 neurons against oxidative stress induced by glutamate. In results, the pretreatment of MLC significantly enhanced the viability of HT-22 cells under glutamate-induced oxidative conditions, suggesting that MLC has a neuronal mechanism to protect neurons without microglial regulation. Also, the glutamate effect to increase ROS production was effectively blocked by MLC without any free radical scavenging activity. To induce this antioxidant effect, MLC upregulated the expression of heme oxygenase 1 (HO-1) and nuclear translocation of nuclear factor-E2-related factor 2 (Nrf-2), known as an intracellular antioxidant enzyme, and its transcription factor. Additionally, Akt phosphorylation regulating Nrf-2 was confirmed to be involved in the neuroprotective signaling activated by MLC. These results indicate that MLC may play a role as an antioxidant agent to inhibit neurodegenerative processes via activating antioxidant signaling pathways that include Nrf-2 and phosphatidylinositol 3-kinase (PI3K).

A‐type K⁺ channels (I_A channels) contribute to learning and memory mechanisms by regulating neuronal excitabilities in the CNS, and their expression level is targeted by Ca²⁺ influx via synaptic NMDA receptors (NMDARs) during long‐term potentiation (LTP). However, it is not clear how local synaptic Ca²⁺ changes induce I_A downregulation throughout the neuron, extending from the active synapse to the soma. In this study, we tested if two major receptors of endoplasmic reticulum (ER), ryanodine (RyRs), and IP₃ (IP₃R) receptors, are involved in Ca²⁺‐mediated I_A downregulation in cultured hippocampal neurons of rats. The downregulation of I_A channels was induced by doubling the Ca²⁺ concentration in culture media (3.6 mM for 24 hrs) or treating with glycine (200 μM for 3 min) to induce chemical LTP (cLTP), and the changes in I_A peaks were measured electrophysiologically by a whole‐cell patch. We confirmed that Ca²⁺ or glycine treatment significantly reduced I_A peaks and that their effects were abolished by blocking NMDARs or voltage‐dependent Ca²⁺ channels (VDCCs). In this cellular processing, blocking RyRs (by ryanodine, 10 μM) but not IP₃Rs (by 2APB, 100 μM) completely abolished I_A downregulation, and the LTP observed in hippocampal slices was more diminished by ryanodine rather than 2APB. Furthermore, blocking RyRs also reduced Ca²⁺‐mediated PKA activation, indicating that sequential signaling cascades, including the ER and PKA, are involved in regulating I_A downregulation. These results strongly suggest a possibility that RyR contribution and mediated I_A downregulation are required to regulate membrane excitability as well as synaptic plasticity in CA3‐CA1 connections of the hippocampus.

Yang YS, et al. Korean J Physiol Pharmacol. 2017 Mar;21(2):259-265. https://doi.org/10.4196/kjpp.2017.21.2.259

Cui Y, et al. Korean J Physiol Pharmacol. 2015 May;19(3):219-228. http://dx.doi.org/10.4196/kjpp.2015.19.3.219

In the mammalian brain, information encoding and storage have been explained by revealing the cellular and molecular mechanisms of synaptic plasticity at various levels in the central nervous system, including the hippocampus and the cerebral cortices. The modulatory mechanisms of synaptic excitability that are correlated with neuronal tasks are fundamental factors for synaptic plasticity, and they are dependent on intracellular Ca²⁺-mediated signaling. In the present review, the A-type K⁺ (I _A) channel, one of the voltage-dependent cation channels, is considered as a key player in the modulation of Ca²⁺ influx through synaptic NMDA receptors and their correlated signaling pathways. The cellular functions of I _A channels indicate that they possibly play as integral parts of synaptic and somatic complexes, completing the initiation and stabilization of memory.

Kang MS, et al. Korean J Physiol Pharmacol. 2014 Apr;18(2):135-141. https://doi.org/10.4196/kjpp.2014.18.2.135