Toxicity, Deficiency and Dysmetabolism of Trace Elements in Ghanaian Clinically Stable Schizophrenics

AIM: The purpose of the study was to determine the levels of Copper (Cu), selenium (Se), Zinc (Zn), Lead (Pb) and Lithium (Li) in patients in Accra and Pantang Psychiatric Hospitals in Ghana since no data exist.SUBJECTS AND METHODS: Simple random sampling of age-matched subjects was used to recruit 81 schizophrenics and 25 mentally healthy controls in 2012. Serum levels of Cu, Se, Zn, Pb and Li were determined by flame atomic absorption spectroscopy (FAAS). RESULTS: Mean levels were as follows: Cut 766 ± 250 µg/L and Cuc 855 ± 270 µg/L (p = 0.168). Set 149 ± 72 µg/L and Sec 108 ± 61 µg/L (p=0.009). Znt 702 ± 438 µg/L and Znc 1007 ± 593 µg/L (p = 0.028). Pbt 1.38 ± 0.05 µg/L and Pbc 0.10 ± 0.05 µg/L (p = 0.000). Li levels for the test group (Lit) was 4077 ± 2567 µg/L, whiles that of the controls was undetectable < 0.02 µg/L. Se, Pb and Li levels were significantly higher in schizophrenic patients compared to controls. While Zn and Cu levels were lower in the same group.CONCLUSION: Trace elements dysmetabolism exist among Ghanaian schizophrenics and monitoring is essential to avoid the adverse effects of metal overload or deficiency

In Vitro Analyses of Novel HCN4 Gene Mutations

Background/Aims: The hyperpolarization-activated cyclic nucleotide-gated cation channel HCN4 contributes significantly to the generation of basic cardiac electrical activity in the sinus node and is a mediator of modulation by β–adrenergic stimulation. Heterologous expression of sick sinus syndrome (SSS) and bradycardia associated mutations within the human HCN4 gene results in altered channel function. The main aim was to describe the functional characterization of three (two novel and one known) missense mutations of HCN4 identified in families with SSS. Methods: Here, the two-electrode voltage clamp technique on Xenopus laevis oocytes and confocal imaging on transfected COS7 cells respectively, were used to analyze the functional effects of three HCN4 mutations; R378C, R550H, and E1193Q. Membrane surface expressions of wild type and the mutant channels were assessed by confocal microscopy, chemiluminescence assay, and Western blot in COS7 and HeLa cells. Results: The homomeric mutant channels R550H and E1193Q showed loss of function through increased rates of deactivation and distinctly reduced surface expression in all three homomeric mutant channels. HCN4 channels containing R550H and E1193Q mutant subunits only showed minor effects on the voltage dependence and rates of activation/deactivation. In contrast, homomeric R378C exerted a left-shifted activation curve and slowed activation kinetics. These effects were reduced in heteromeric co-expression of R378C with wild-type (WT) channels. Conclusion: Dysfunction of homomeric/heteromeric mutant HCN4-R378C, R550H, and E1193Q channels in the present study was primarily caused by loss of function due to decreased channel surface expression

The Natural Plant Product Rottlerin Activates Kv7.1/KCNE1 Channels

Background/Aims: Acquired as well as inherited channelopathies are disorders that are caused by altered ion channel function. A family of channels whose malfunction is associated with different channelopathies is the Kv7 K+ channel family; and restoration of normal Kv7 channel function by small molecule modulators is a promising approach for treatment of these often fatal diseases. Methods: Here, we show the modulation of Kv7 channels by the natural compound Rottlerin heterologously expressed in Xenopus laevis oocytes and on iPSC cardiomyocytes overexpressing Kv7.1 channels. Results: We show that currents carried by Kv7.1 (EC50 = 1.48 μM), Kv7.1/KCNE1 (EC50 = 4.9 μM), and Kv7.4 (EC50 = 0.148 μM) are strongly enhanced by the compound, whereas Kv7.2, Kv7.2/Kv7.3, and Kv7.5 are not sensitive to Rottlerin. Studies on Kv7.1/KCNE1 mutants and in silico modelling indicate that Rottlerin binds to the R-L3-activator site. Rottlerin mediated activation of Kv7.1/KCNE1 channels might be a promising approach in long QT syndrome. As a proof of concept, we show that Rottlerin shortens cardiac repolarisation in iPSC-derived cardiomyocytes expressing Kv7.1.Conclusion: Rottlerin or an optimized derivative holds a potential as QT interval correcting drug

The natural plant product Rottlerin activates Kv7.1/KCNE1 channels

$\textit {Background/Aims:}$ Acquired as well as inherited channelopathies are disorders that are caused by altered ion channel function. A family of channels whose malfunction is associated with different channelopathies is the Kv7 $K^{+}$ channel family; and restoration of normal Kv7 channel function by small molecule modulators is a promising approach for treatment of these often fatal diseases. $\textit {Methods:}$ Here, we show the modulation of Kv7 channels by the natural compound Rottlerin heterologously expressed in $\textit {Xenopus laevisoocytes}$ and on iPSC cardiomyocytes overexpressing Kv7.1 channels. $\textit {Results:}$ We show that currents carried by Kv7.1 ($EC_{50}$ = 1.48 $\mu$M), Kv7.1/KCNE1 ($EC_{50}$ = 4.9 $\mu$M), and Kv7.4 ($EC_{50}$ = 0.148 $\mu$M) are strongly enhanced by the compound, whereas Kv7.2, Kv7.2/Kv7.3, and Kv7.5 are not sensitive to Rottlerin. Studies on Kv7.1/KCNE1 mutants and in silico modelling indicate that Rottlerin binds to the R-L3-activator site. Rottlerin mediated activation of Kv7.1/KCNE1 channels might be a promising approach in long QT syndrome. As a proof of concept, we show that Rottlerin shortens cardiac repolarisation in iPSC-derived cardiomyocytes expressing Kv7.1. $\textit {Conclusion:}$ Rottlerin or an optimized derivative holds a potential as QT interval correcting drug