• Bulletin of the Korean Chemical Society
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• v.32 no.spc8
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• pp.3063-3073
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• 2011

The synthesis and biological evaluation of 1-heteroarylmethyl 1,4-diazepane derivatives as potential T-type calcium channel blockers is described. In this study, we have identified the compound 21i exhibiting the most potent T-type calcium channel blocking activity with $IC_{50}$ value of 0.20 ${\mu}M$, which is superior to that of mibefradil.

• Journal of Food Hygiene and Safety
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• v.13 no.3
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• pp.258-267
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• 1998

The acetaminophen (AP AP), an antipyretic and analgesic agent, induces the hepatotoxicity by increasing influx of calcium and destabilizing the cellular membrane which can be caused by N-acetyl-p-benzoquinoneimine generated by cytochrome P-450 (CYF-450) when it is overdosed. Diltiazem (DIL), a calcium channel blocking agent, has been known to suppress the CYF-450 activities. To study the effect of DIL in APAP treated rats, the serum biotransformational enzyme analyses and the liver histopathologic examination were conducted on the rats which had been administered DIL at 3, 6, 9 and 12 hours after the 3,000 mg/kg of APAP administration. Following a single dose of DIL administered 12 hours after AP AP administration, serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) activities, malondialdehyde and calcium contents of liver and microsome were significantly reduced. Glutathione S-transferase (GST) activity was significantly increased. Histopathologic studies showed that DIL had prevented the development of centrilobular necrosis induced by AP AP in liver tissue. Our results suggested that diltiazem could inhibit the formation of free radical and the influx of calcium and could increase GST activity. Therefore, diltiazem can be administered at the time of 12 hours after overdosed AP AP to diminish the liver damage.

• Archives of Pharmacal Research
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• v.14 no.3
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• pp.271-278
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• 1991

To investigate further whether the effects of the dihydropyridine (DHP) drugs on calcium channels are related to those of these drugs on muscarinic receptors, the binding characteristics of the DHP calcium channel agonist, Bay K 8644, on muscarinic receptors and calcium channels were compared to those of the DHP calcium channel antagonists, nicardipine and nimodipine in the dog cardiac sarcolemma. Bay K 8644, nicardipine and nimodipine inhibited the specific $[^3H]$QNB binding with $K_i$ values of 16.7\mu{M}$, 3.5\mu{M}$ and 15.5\mu{M}$ respectively. Saturation data of $[^3H]$QNB binding with $K_i$ VALUES OF 16.7\mu{M}$ 3.5\mu{M}$ and 15.5\mu{M}$ respectively. Saturation data of $[^3H]$QNB binding in the presence of these DHP drugs showed this inhibition to be competitive. Bay K 8644, like nicardipine and nimodipine, blocked the binding of $[^3H]$nitrendipine to the high affinity DHP binding sites, but atropine did not, indicating that the muscarinic receptors and the DHP binding sites m but atropine did not, indicating that the muscarinic receptors and the DHP bindings sites on calcium channels are distinct. The $K_i$ value of Bay K 8644 for the DHP binding sites was 4nM. Nicardipine and nimodipine $(K_i:0.1-0.2\;nM)$ were at least 20 times more potent than Bay K 8644 in inhibiting $[^3H]$ nitrendipine binding. Thus, the muscarinic receptors were about 4000 times less sensitive than thes high afinity DHP binding sites to Bay K 8644. These results suggest that the DHP calcium agonist Bay K 8644 binds directly to the muscarinic receptors but its interaction with the muscarinic receptors is not related to its binding to the DHP binding sites on calcium channels.

• The Korean Journal of Physiology and Pharmacology
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• v.1 no.6
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• pp.625-637
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• 1997

Calcium ions are implicated in a variety of physiological functions, including enzyme activity, membrane excitability, neurotransmitter release, and synaptic transmission, etc. Calcium antagonists have been known to be effective for the treatment of exertional angina and essential hypertension. Selective and nonselective voltage-dependent calcium channel blockers also have inhibitory action on the acute and tonic pain behaviors resulting from thermal stimulation, subcutaneous formalin injection and nerve injury. This study was undertaken to investigate the effects of iontophoretically applied $Ca^{++}$ and its antagonists on the responses of WDR (wide dynamic range) cells to sensory inputs. The responses of WDR cells to graded electrical stimulation of the afferent nerve and also to thermal stimulation of the receptive field were recorded before and after iontophoretical application of $Ca^{++}$, EGTA, $Mn^{++}$, verapamil, ${\omega}-conotoxin$ GVIA, ${\omega}-conotoxin$ MVIIC and ${\omega}-agatoxin$ IVA. Also studied were the effects of a few calcium antagonists on the C-fiber responses of WDR cells sensitized by subcutaneous injection of mustard oil (10%). Calcium ions and calcium channel antagonists ($Mn^{++}$, verapamil, ${\omega}-conotoxin$ GVIA & ${\omega}-agatoxin$ IVA) current-dependently suppressed the C-fiber responses of WDR cells without any significant effects on the A-fiber responses. But ${\omega}-conotoxin$ MVIIC did not have any inhibitory actions on the responses of WDR cell to A-fiber, C-fiber and thermal stimulation. Iontophoretically applied EGTA augmented the WDR cell responses to C-fiber and thermal stimulations while spinal application of EGTA for about $20{\sim}30\;min$ strongly inhibited the C-fiber responses. The augmenting and the inhibitory actions of EGTA were blocked by calcium ions. The WDR cell responses to thermal stimulation of the receptive field were reduced by iontophoretical application of $Ca^{++}$, verapamil, ${\omega}-agatoxin$ IVA, and ${\omega}-conotoxin$ GVIA but not by ${\omega}-conotoxin$ MVIIC. The responses of WDR cells to C-fiber stimulation were augmented after subcutaneous injection of mustard oil (10%, 0.15 ml) into the receptive field and these sensitized C-fiber responses were strongly suppressed by iontophoretically applied $Ca^{++}$, verapamil, ${\omega}-conotoxin$ GVIA and ${\omega}-agatoxin$ IVA. These experimental findings suggest that in the rat spinal cord, L-, N-, and P-type, but not Q-type, voltage-sensitive calcium channels are implicated in the calcium antagonist-induced inhibition of the normal and the sensitized responses of WDR cells to C-fiber and thermal stimulation, and that the suppressive effect of calcium and augmenting action of EGTA on WDR cell responses are due to changes in excitability of the cell.

• The Korean Journal of Physiology and Pharmacology
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• v.24 no.3
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• pp.277-286
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• 2020

Polycystic kidney disease 2-like-1 (PKD2L1), also known as polycystin-L or TRPP3, is a non-selective cation channel that regulates intracellular calcium concentration. Calmodulin (CaM) is a calcium binding protein, consisting of N-lobe and C-lobe with two calcium binding EF-hands in each lobe. In previous study, we confirmed that CaM is associated with desensitization of PKD2L1 and that CaM N-lobe and PKD2L1 EF-hand specifically are involved. However, the CaM-binding domain (CaMBD) and its inhibitory mechanism of PKD2L1 have not been identified. In order to identify CaM-binding anchor residue of PKD2L1, single mutants of putative CaMBD and EF-hand deletion mutants were generated. The current changes of the mutants were recorded with whole-cell patch clamp. The calmidazolium (CMZ), a calmodulin inhibitor, was used under different concentrations of intracellular. Among the mutants that showed similar or higher basal currents with that of the PKD2L1 wild type, L593A showed little change in current induced by CMZ. Co-expression of L593A with CaM attenuated the inhibitory effect of PKD2L1 by CaM. In the previous study it was inferred that CaM C-lobe inhibits channels by binding to PKD2L1 at 16 nM calcium concentration and CaM N-lobe at 100 nM. Based on the results at 16 nM calcium concentration condition, this study suggests that CaM C-lobe binds to Leu-593, which can be a CaM C-lobe anchor residue, to regulate channel activity. Taken together, our results provide a model for the regulation of PKD2L1 channel activity by CaM.

• Proceedings of the Zoological Society Korea Conference
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• 1998.04a
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• pp.54.2-54
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• 1998

No Abstract, See Full Text

• BMB Reports
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• v.55 no.11
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• pp.528-534
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• 2022

Mitochondria are cellular organelles that perform various functions within cells. They are responsible for ATP production, cell-signal regulation, autophagy, and cell apoptosis. Because the mitochondrial proteins that perform these functions need Ca²⁺ ions for their activity, mitochondria have ion channels to selectively uptake Ca²⁺ ions from the cytoplasm. The ion channel known to play the most important role in the Ca²⁺ uptake in mitochondria is the mitochondrial calcium uniporter (MCU) holo-complex located in the inner mitochondrial membrane (IMM). This ion channel complex exists in the form of a complex consisting of the pore-forming protein through which the Ca²⁺ ions are transported into the mitochondrial matrix, and the auxiliary protein involved in regulating the activity of the Ca²⁺ uptake by the MCU holo-complex. Studies of this MCU holo-complex have long been conducted, but we didn't know in detail how mitochondria uptake Ca²⁺ ions through this ion channel complex or how the activity of this ion channel complex is regulated. Recently, the protein structure of the MCU holo-complex was identified, enabling the mechanism of Ca²⁺ uptake and its regulation by the MCU holo-complex to be confirmed. In this review, I will introduce the mechanism of action of the MCU holo-complex at the molecular level based on the Cryo-EM structure of the MCU holo-complex to help understand how mitochondria uptake the necessary Ca²⁺ ions through the MCU holo-complex and how these Ca²⁺ uptake mechanisms are regulated.

• BMB Reports
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• v.53 no.3
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• pp.125-132
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• 2020

Transient receptor potential (TRP) channels comprise a diverse family of ion channels, the majority of which are calcium permeable and show sophisticated regulatory patterns in response to various environmental cues. Early studies led to the recognition of TRP channels as environmental and chemical sensors. Later studies revealed that TRP channels mediated the regulation of intracellular calcium. Mutations in TRP channel genes result in abnormal regulation of TRP channel function or expression, and interfere with normal spatial and temporal patterns of intracellular local Ca²⁺ distribution. The resulting dysregulation of multiple downstream effectors, depending on Ca²⁺ homeostasis, is associated with hallmarks of cancer pathophysiology, including enhanced proliferation, survival and invasion of cancer cells. These findings indicate that TRP channels affect multiple events that control cellular fate and play a key role in cancer progression. This review discusses the accumulating evidence supporting the role of TRP channels in tumorigenesis, with emphasis on prostate cancer.

• Archives of Pharmacal Research
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• v.18 no.6
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• pp.402-409
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• 1995

The effects of calcium channel blockers (CAB's) verapamil, diltiazem and nicardipine, on erythrocyte ghost membranes have been studied. Using the fluorospectroscopic method, it was observed that the fluidity of the inner layer of ghost membranes was increased with an increase of drug concentrations but did not any changes in the fluidity of the outer layer. These drugs showed protectuve effect against hypotonic hemolysis of erythrocytes. Thus, the expansion of surface area in response to corpuscular volume of erythrocytes in the presence of CAB's is seemed to play an important role in protecting hypotonic hemolysis of erythrocytes.

• The Korean Journal of Physiology and Pharmacology
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• v.24 no.1
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• pp.101-110
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• 2020

Transient receptor potential canonical 4 (TRPC4) channel is a nonselective calcium-permeable cation channels. In intestinal smooth muscle cells, TRPC4 currents contribute more than 80% to muscarinic cationic current (mIcat). With its inward-rectifying current-voltage relationship and high calcium permeability, TRPC4 channels permit calcium influx once the channel is opened by muscarinic receptor stimulation. Polyamines are known to inhibit nonselective cation channels that mediate the generation of mIcat. Moreover, it is reported that TRPC4 channels are blocked by the intracellular spermine through electrostatic interaction with glutamate residues (E728, E729). Here, we investigated the correlation between the magnitude of channel inactivation by spermine and the magnitude of channel conductance. We also found additional spermine binding sites in TRPC4. We evaluated channel activity with electrophysiological recordings and revalidated structural significance based on Cryo-EM structure, which was resolved recently. We found that there is no correlation between magnitude of inhibitory action of spermine and magnitude of maximum current of the channel. In intracellular region, TRPC4 attracts spermine at channel periphery by reducing access resistance, and acidic residues contribute to blocking action of intracellular spermine; channel periphery, E649; cytosolic space, D629, D649, and E687.