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In many addictive drugs including alcohol and nicotine, proarrhythmic effects were reported. This review provides an overview of the current knowledge in this field (with a focus on the inward rectifier potassium currents) to promote the lacking data and appeal for their completion, thus, to improve understanding of the proarrhythmic potential of addictive drugs. [ABSTRACT FROM AUTHOR]

Aims One form of the short QT syndrome (SQT3) has been linked to the D172N gain-in-function mutation to Kir2.1, which preferentially increases outward current through channels responsible for inward rectifier K+ current (IK1). This study investigated mechanisms by which the Kir2.1 D172N mutation facilitates and perpetuates ventricular arrhythmias. Methods and results The ten Tusscher et al. model for human ventricular action potentials (APs) was modified to incorporate changes to IK1 based on experimentally observed changes to Kir2.1 function: both heterozygous (WT-D172N) and homozygous (D172N) mutant scenarios were studied. Cell models were incorporated into heterogeneous one-dimensional (1D), 2D tissue, and 3D models to compute the restitution curves of AP duration (APD-R), effective refractory period (ERP-R), and conduction velocity (CV). Temporal and spatial vulnerability of ventricular tissue to re-entry was measured and dynamic behaviour of re-entrant excitation waves (lifespan and dominant frequency) in 2D and 3D models of the human ventricle was characterized. D172N ‘mutant’ IK1 led to abbreviated APD and ERP, as well as steeper APD-R and ERP-R curves. It reduced tissue excitability at low excitation rates but increased it at high rates. It increased tissue temporal vulnerability for initiating re-entry, but reduced the minimal substrate size necessary to sustain re-entry. SQT3 ‘mutant’ IK1 also stabilized and accelerated re-entrant excitation waves, leading to sustained rapid re-entry. Conclusion Increased IK1 due to the Kir2.1 D172N mutation increases arrhythmia risk due to increased tissue vulnerability, shortened ERP, and altered excitability, which in combination facilitate initiation and maintenance of re-entrant circuits. [ABSTRACT FROM PUBLISHER]

The family of voltage-gated (Shaker-like) potassium channels in plants includes both inward-rectifying (Kin) channels that allow plant cells to accumulate K+ and outward-rectifying (Kout) channels that mediate K+ efflux. Despite their close structural similarities, Kin and Kout channels differ in their gating sensitivity towards voltage and the extracellular K+ concentration. We have carried out a systematic program of domain swapping between the Kout channel SKOR and the Kin channel KAT1 to examine the impacts on gating of the pore regions, the S4, S5, and the S6 helices. We found that, in particular, the N-terminal part of the S5 played a critical role in KAT1 and SKOR gating. Our findings were supported by molecular dynamics of KAT1 and SKOR homology models. In silico analysis revealed that during channel opening and closing, displacement of certain residues, especially in the S5 and S6 segments, is more pronounced in KAT1 than in SKOR. From our analysis of the S4–S6 region, we conclude that gating (and K+-sensing in SKOR) depend on a number of structural elements that are dispersed over this ∼145-residue sequence and that these place additional constraints on configurational rearrangement of the channels during gating. [ABSTRACT FROM PUBLISHER]

Objective: The Andersen’s syndrome is a hereditary disease, which is characterized by cardiac arrhythmias, periodic paralysis and dysmorphic features. Recently, mutations of the KCNJ2 gene, which encodes the inward rectifying potassium channel subunit Kir2.1, have been identified in affected individuals. However, the functional effects of these mutations have not yet been fully elucidated. Methods and Results: To clarify this situation we generated known Andersen disease mutants of KCNJ2 which did not yield any measurable K+ currents in CHO cells indicating that the Andersen mutants failed to form functional homomultimeric complexes. EGFP-tagged KCNJ2 wild-type and mutant channels distributed in a similar homogeneous pattern in the cell membrane suggesting that protein trafficking was not altered by the Andersen mutations but rather implicating that the mutations rendered the KCNJ2 channel non-functional. In heterologous coexpression experiments the Andersen mutants exerted a dominant-negative effect on wild-type KCNJ2. However, the extent of suppression varied between the different KCNJ2 mutants. Given our results in CHO cells, we expressed the disease mutant KCNJ2-S136F in neonate rat cardiomyocytes using adenoviral gene transfer to test the effect of Andersen mutants on native IK1. IK1 density was indeed significantly reduced in KCNJ2-S136F-infected cells (n=9) compared to control cells (n=9) over a voltage range from −70 to −150 mV (P<0.05). Conclusion: These results support that Kir2.x channels are a critical component of native IK1 in neonate rat cardiomyocytes and that a dominant-negative suppression of IK1 in native cells is the pathophysiological correlate of the Andersen’s syndrome. [Copyright &y& Elsevier]

Structure-function relationships of voltage-dependent ion channels have been analysed by site-directed mutagenesis and functional electrophysiological characterizations. A complementary genetic selection approach for identifying interesting K+ channel mutations, allowing selection from a large random pool of K+ channel mutants, is described here. Non-inactivating inward-rectifying potassium channels provide an important mechanism for K+ uptake into plant cells. The Arabidopsis Kin+ channel, KAT1, functionally complements a yeast strain deficient in K+ uptake. The alkali metal Cs+ blocks Kin+ channels and inhibits growth of yeast cells expressing KAT1. In this study a mutagenesis method called 'DNA shuffling' (or 'recombinant PCR') was applied to generate random mutants in the KAT1 channel. Randomly mutated libraries of KAT1 were expressed in yeast and Cs+-resistant colonies were selected. KAT1 mutants that conferred a Cs+-resistant phenotype for yeast growth were functionally characterized by expression in Xenopus oocytes and two electrode voltage clamp analysis. K+ channel properties, such as Cs+-block sensitivity, cation selectivity, and steady-state activation were altered by mutating amino acids in the pore region, but also in regions adjacent to the pore region of the KAT1 channel. Amino acid substitutions previously not targeted for site-directed mutagenesis were identified that affect Cs+ block of K+ channels. Two amino acid positions, 1209 in the S5 domain and E269, were mutated in more than one of the Cs+-resistant mutants indicating important roles in Cs+ sensitivity. Shifts in steady-state activation and/or resistance to block by Cs+ were determined to be mechanisms which contribute to the Cs+ resistance of the selected mutants. [ABSTRACT FROM PUBLISHER]

Objective: Capsaicin is a pungent irritant present in peppers of the Capsicum family. Its major target of action is believed to be sensory neurones. Capsaicin has also been shown to prolong cardiac action potential in atrial muscle, perhaps by local release of calcitonin gene related peptide which in turn enhances inward calcium currents. However, capsaicin has been shown to inhibit K+ currents in neurones. Since such an action could contribute to action potential prolonging activity of capsaicin in heart, the aim of the study was to examine the effects of capsaicin on cardiac K+ currents. Methods: Ionic currents and action potentials were examined in isolated adult rat ventricular myocytes using the whole cell variant of the patch clamp technique at 25°C. Results: Capsaicin (10 |xM) increased the action potential duration (APD50) from 45 ms to 166 ms. This effect was associated with an inhibition of three distinct K+ currents. The decreasing rank order of potency was: transient outward K+ current (Ito, IC50=6.4 (μM), a voltage dependent non-inactivating outward current (IK, IC50=11.5 μM), and the inward rectifier K+ current (IKI, IC50=46.9 μM). Capsaicin induced block of Ito was characterised by a decrease in the peak current amplitude and an increase in the rate of inactivation. The inactivation of ITO in the absence of capsaicin was well described by a single exponential [τ=77 (SEM 2) ms at +40 mV, n=10]. However, in the presence of 10 μM capsaicin inactivation was best described by the sum of two exponentials [τFAST=4.4(0.5) ms; τSLOW=92.4(3.0) ms, n=10] with the fast component contributing 46(2)% of the total decay. A small but consistent hyperpolarising shift (∼3 mV) in the steady state voltage dependence of inactivation of ITO was induced by 10 μM capsaicin. Capsaicin had no effect on the rate of Ito recovery from inactivation (τ=49 ms and 48 ms for control and drug respectively). The capsaicin analogue, resiniferatoxin, which as an irritant is up to 104-fold more potent than capsaicin, had no effect on any of the K+ currents when present at concentrations of up to 10 μM. In contrast another capsaicin analogue, zingerone (30 μM) blocked Ito by 52(12)% and IK by 35%. Conclusions: Capsaicin produces a prolongation of the rat ventricular action potential, an effect which is associated with inhibition of potassium currents.Cardiovascular Research 1992;26:1137-1144 [ABSTRACT FROM PUBLISHER]