Regulation of Human Kv1.4 Channel Activity by the Antidepressant Metergoline

Yeom, Hye Duck; Lee, Jiae

doi:10.1248/bpb.b16-00069

Cited by 6 publications

(4 citation statements)

References 14 publications

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“…Regulators of 5-HT serotonin receptors modulate macrophage cytokines, mitigate infection with bacteria and fungi in macrophages and mice [21,[84][85][86], and inhibit RND efflux pumps in E. coli [87,88]. In addition, metergoline inhibits sodium/potassium channels in Xenopus laevis and human cells [89][90][91]. These findings suggest that metergoline has pleiotropic effects in bacteria and eukaryotes.…”

Section: Plos Pathogensmentioning

confidence: 99%

A small molecule that mitigates bacterial infection disrupts Gram-negative cell membranes and is inhibited by cholesterol and neutral lipids

et al. 2020

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Infections caused by Gram-negative bacteria are difficult to fight because these pathogens exclude or expel many clinical antibiotics and host defense molecules. However, mammals have evolved a substantial immune arsenal that weakens pathogen defenses, suggesting the feasibility of developing therapies that work in concert with innate immunity to kill Gram-negative bacteria. Using chemical genetics, we recently identified a small molecule, JD1, that kills Salmonella enterica serovar Typhimurium (S. Typhimurium) residing within macrophages. JD1 is not antibacterial in standard microbiological media, but rapidly inhibits growth and curtails bacterial survival under broth conditions that compromise the outer membrane or reduce efflux pump activity. Using a combination of cellular indicators and super resolution microscopy, we found that JD1 damaged bacterial cytoplasmic membranes by increasing fluidity, disrupting barrier function, and causing the formation of membrane distortions. We quantified macrophage cell membrane integrity and mitochondrial membrane potential and found that disruption of eukaryotic cell membranes required approximately 30-fold more JD1 than was needed to kill bacteria in macrophages. Moreover, JD1 preferentially damaged liposomes with compositions similar to E. coli inner membranes versus mammalian cell membranes. Cholesterol, a component of mammalian cell membranes, was protective in the presence of neutral lipids. In mice, intraperitoneal administration of JD1 reduced tissue colonization by S. Typhimurium. These observations indicate that during infection, JD1 gains access to and disrupts the cytoplasmic membrane of Gram-negative bacteria, and that neutral lipids and cholesterol protect mammalian membranes from JD1-mediated damage. Thus, it may be possible to develop therapeutics that exploit host innate immunity to gain access to Gram-negative bacteria and then preferentially damage the bacterial cell membrane over host membranes.

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Section: Plos Pathogensmentioning

confidence: 99%

A small molecule that mitigates bacterial infection disrupts Gram-negative cell membranes and is inhibited by cholesterol and neutral lipids

et al. 2020

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“…Among them, K V 1.2 is mostly in the central nervous system, and K V 1.3 is more prominent in peripheral tissues. K V 1.4, an A-type K V channel, is widely distributed in excitable cells of mammalian tissues and exists in the cardiac ventricular endocardium [ 18 , 19 ]. The inhibitory effects of 2-APB on three channels can be used to explain the effects of 2-APB on the human body and animal models of human disease.…”

Section: Discussionmentioning

confidence: 99%

Inhibitory Effects of 2-Aminoethoxydiphenyl Borate (2-APB) on Three KV1 Channel Currents

et al. 2023

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2-Aminoethoxydiphenyl borate (2-APB), a boron-containing compound, is a multitarget compound with potential as a drug precursor and exerts various effects in systems of the human body. Ion channels are among the reported targets of 2-APB. The effects of 2-APB on voltage-gated potassium channels (KV) have been reported, but the types of KV channels that 2-APB inhibits and the inhibitory mechanism remain unknown. In this paper, we discovered that 2-APB acted as an inhibitor of three representative human KV1 channels. 2-APB significantly blocked A-type Kv channel KV1.4 in a concentration-dependent manner, with an IC50 of 67.3 μM, while it inhibited the delayed outward rectifier channels KV1.2 and KV1.3, with IC50s of 310.4 μM and 454.9 μM, respectively. Further studies on KV1.4 showed that V549, T551, A553, and L554 at the cavity region and N-terminal played significant roles in 2-APB’s effects on the KV1.4 channel. The results also indicated the importance of fast inactivation gating in determining the different effects of 2-APB on three channels. Interestingly, a current facilitation phenomenon by a short prepulse after 2-APB application was discovered for the first time. The docked modeling revealed that 2-APB could form hydrogen bonds with different sites in the cavity region of three channels, and the inhibition constants showed a similar trend to the experimental results. These findings revealed new molecular targets of 2-APB and demonstrated that 2-APB’s effects on KV1 channels might be part of the reason for the diverse bioactivities of 2-APB in the human body and in animal models of human disease.

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“…The treatment of oocytes and mutagenesis were described in previous study [ 13 ]. Briefly, frogs caring procedures were followed by the Jonnam National University animal caring institute guidelines (JNU IACUC-YB-2017-07, July 2017).…”

Section: Methodsmentioning

confidence: 99%

“…The data analysis was described in previous study [ 13 ]. To acquire dose dependent curves for the effects of gomisin A on capsaicin-induced current, the induced peak currents at each gomisin A concentration were plotted using the Hill equation.…”

Section: Methodsmentioning

confidence: 99%

A Molecular Basis for the Inhibition of Transient Receptor Potential Vanilloid Type 1 by Gomisin A

Lee

Noh

Yeom

et al. 2017

Evidence-Based Complementary and Alternative Medicine

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Transient receptor potential (TRP) channel has critical actions as conditional sensors in primary afferent neurons. We studied the regulatory action of gomisin A on TRPV1 channel current in this report. Schisandra chinensis contains bioactive compounds such as the gomisin derivatives and their related compounds. Coapplication with gomisin A inhibited the capsaicin-mediated inward peak current. This inhibitory effect of gomisin A on capsaicin-induced inward current showed concentration-dependence and was reversible. The half maximal inhibitory concentration of gomisin A was 62.7 ± 8.4 µM. In addition, this inhibition occurred in a noncompetition regulation mode and voltage insensitive manner. Furthermore, molecular docking studies of gomisin A on TRPV1 showed that it interacted predominantly with residues at cavities in the segments 1 and 2 of each subunit. Four potential binding sites for this ligand in the extracellular region at sensor domain of TRPV1 channel were identified. Point mutagenesis studies were undertaken, and gomisin A potency decreased for both the Y453A and N467A mutants. The double mutation of Y453 and N467 significantly attenuated inhibitory effects by gomisin A. In summary, this study revealed the molecular basis for the interaction between TRPV1 and gomisin A and provides a novel potent interaction ligand.

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Regulation of Human Kv1.4 Channel Activity by the Antidepressant Metergoline

Cited by 6 publications

References 14 publications

A small molecule that mitigates bacterial infection disrupts Gram-negative cell membranes and is inhibited by cholesterol and neutral lipids

A small molecule that mitigates bacterial infection disrupts Gram-negative cell membranes and is inhibited by cholesterol and neutral lipids

Inhibitory Effects of 2-Aminoethoxydiphenyl Borate (2-APB) on Three KV1 Channel Currents

A Molecular Basis for the Inhibition of Transient Receptor Potential Vanilloid Type 1 by Gomisin A

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