Ion Channel Currents Research Articles

A range of voltage-clamp protocol designs for rapid capture of hERG kinetics

We provide details of a series of short voltage-clamp protocols designed for gathering a large amount of information on hERG (Kv11.1) ion channel gating. The protocols have a limited number of steps and consist only of steps and ramps, making them easy to implement on any patch clamp setup, including automated platforms. The primary objective is to assist with parameterisation, selection and refinement of mathematical models of hERG gating. We detail a series of manual and automated model-driven designs, together with an explanation of their rationale and design criteria. Although the protocols are intended to study hERG1a currents, the approaches could be easily extended and generalised to other ion channel currents.

Dynamical effects of low-frequency and high-frequency current stimuli in a memristive Morris–Lecar neuron model

This paper deduces that the potassium and calcium ion currents in the two-dimensional (2D) Morris–Lecar neuron model can be respectively characterized by a passive memristor and a locally active memristor. Then a memristive Morris–Lecar neuron model with an equivalent circuit scheme is first constructed. The equilibrium trajectory and its stability are analyzed, which displays fold and Hopf bifurcations with proper model parameters. Bursting behavior and mixed-mode oscillations with after-depolarizing potential for low-frequency current stimulus are numerically disclosed. Besides, the bifurcation mechanisms for bursting behavior and mixed-mode oscillations are theoretically deduced. Furthermore, the firing patterns and antimonotonicity phenomenon for high-frequency current stimulus are numerically discovered. This study provides a new concept for building memristive bionic circuits from neuron models with well-defined ion channel currents.

Analysis of epilepsy-associated variants in HCN3 - Functional implications and clinical observations.

This case study investigates the role of hyperpolarization-activated, cyclic nucleotide-gated (HCN) ion channels, which are integral membrane proteins crucial for regulating neuronal excitability. HCN channels are composed of four subunits (HCN1-4), with HCN1, HCN2, and HCN4 previously linked to epilepsy. However, the role of the HCN3 in epileptogenesis remains underexplored. We recruited a cohort of 298 epilepsy patients to screen for genetic variants in the HCN3 (NM_020897.3) using Sanger sequencing. We identified rare variants and conducted functional assays to evaluate their pathogenicity. We identified three rare heterozygous variants in HCN3: c.1370G > A (R457H), c.1982G > A (R661Q), and c.1982G > A(P630L). Invitro functional analyses demonstrated that these variants affected the expression level of HCN3 protein without altering its membrane localization. Whole-cell voltage-clamp experiments showed that two variants (R457H and R661Q) significantly reduced current density in cells, while P630L has no effect on ion channel current. Our findings suggest that the identified HCN3 genetic variants disrupt HCN ion channel function, highlighting HCN3 as a novel candidate gene involved in epileptic disorders. This expands the genetic landscape of epilepsy and provides new insights into its molecular underpinnings. Epilepsy is a brain disease that can be caused by mutations in specific genes. We found three rare variants in HCN3 gene in 298 patients with epilepsy, and two of the three mutations could be pathogenic and cause epilepsy and another one is single-nucleotide polymorphism, which could have no effect and no contribution to the development of epilepsy.

Computational Modeling of Sodium-Ion-Channel-Based Glucose Sensing Biophysics to Study Cardiac Pacemaker Action Potential

Elevated blood glucose levels, known as hyperglycemia, play a significant role in sudden cardiac arrest, often resulting in sudden cardiac death, particularly among those with diabetes. Understanding the internal mechanisms has been a challenge for healthcare professionals, leading many research groups to investigate the relationship between blood glucose levels and cardiac electrical activity. Our hypothesis suggests that glucose-sensing biophysics mechanisms in cardiac tissue could clarify this connection. To explore this, we adapted a single-compartment computational model of the human pacemaker action potential. We incorporated glucose-sensing mechanisms with voltage-gated sodium ion channels using ordinary differential equations. Parameters for the model were based on existing experimental studies to mimic the impact of glucose levels on pacemaker action potential firing. Simulations using voltage clamp and current clamp techniques showed that elevated glucose levels decreased sodium ion channel currents, leading to a reduction in the pacemaker action potential frequency. In summary, our mathematical model provides a cellular-level understanding of how high glucose levels can lead to bradycardia and sudden cardiac death.

Insulin enhances acid-sensing ion channel currents in rat primary sensory neurons

Insulin has been shown to modulate neuronal processes through insulin receptors. The ion channels located on neurons may be important targets for insulin/insulin receptor signaling. Both insulin receptors and acid-sensing ion channels (ASICs) are expressed in dorsal root ganglia (DRG) neurons. However, it is still unclear whether there is an interaction between them. Therefore, the purpose of this investigation was to determine the effects of insulin on the functional activity of ASICs. A 5 min application of insulin rapidly enhanced acid-evoked ASIC currents in rat DRG neurons in a concentration-dependent manner. Insulin shifted the concentration–response plot for ASIC currents upward, with an increase of 46.2 ± 7.6% in the maximal current response. The insulin-induced increase in ASIC currents was eliminated by the insulin receptor antagonist GSK1838705, the tyrosine kinase inhibitor lavendustin A, and the phosphatidylinositol-3 kinase antagonist wortmannin. Moreover, insulin increased the number of acid-triggered action potentials by activating insulin receptors. Finally, local administration of insulin exacerbated the spontaneous nociceptive behaviors induced by intraplantar acid injection and the mechanical hyperalgesia induced by intramuscular acid injections through peripheral insulin receptors. These results suggested that insulin/insulin receptor signaling enhanced the functional activity of ASICs via tyrosine kinase and phosphatidylinositol-3 kinase pathways. Our findings revealed that ASICs were targets in primary sensory neurons for insulin receptor signaling, which may underlie insulin modulation of pain.

The TREK-1 potassium channel is a potential pharmacological target for vasorelaxation in pulmonary hypertension.

Pulmonary arterial hypertension (PAH) is a progressive disease in which chronic membrane potential (Em) depolarisation of the pulmonary arterial smooth muscle cells (PASMCs) causes calcium overload, a key pathological alteration. Under resting conditions, the negative Em is mainly set by two pore domain potassium (K2P) channels, of which the TASK-1 has been extensively investigated. Ion channel currents and membrane potential of primary cultured human(h) PASMCs were measured using the voltage- and current clamp methods. Intracellular [Ca2+] was monitored using fluorescent microscopy. Pulmonary BP and vascular tone measurements were also performed ex vivo using a rat PAH model. TREK-1 was the most abundantly expressed K2P in hPASMCs of healthy donors and idiopathic(I) PAH patients. Background K+-current was similar in hPASMCs for both groups and significantly enhanced by the TREK activator ML-335. In donor hPASMCs, siRNA silencing or pharmacological inhibition of TREK-1 caused depolarisation, reminiscent of the electrophysiological phenotype of idiopathic PAH. ML-335 hyperpolarised donor hPASMCs and normalised the Em of IPAH hPASMCs. A close link was found between TREK-1 activity and intracellular Ca2+-signalling using a channel activator, ML-335, and an inhibitor, spadin. In the rat, ML-335 relaxed isolated pre-constricted pulmonary arteries and significantly decreased pulmonary arterial pressure in the isolated perfused lung. These data suggest that TREK-1is a key factor in Em setting and Ca2+ homeostasis of hPASMC, and therefore, essential for maintenance of a low resting pulmonary vascular tone. Thus TREK-1 may represent a new therapeutic target for PAH.

Ziprasidone triggers inflammasome signaling via PI3K-Akt-mTOR pathway to promote atrial fibrillation

BackgroundSecond-generation antipsychotics increase the risk of atrial fibrillation. This study explores whether the atypical antipsychotic ziprasidone triggers inflammasome signaling, leading to atrial arrhythmia. MethodsElectromechanical and pharmacological assessments were conducted on the rabbit left atria (LA). The patch-clamp technique was used to measure ionic channel currents in single cardiomyocytes. Detection of cytosolic reactive oxygen species production was performed in atrial cardiomyocytes. ResultsThe duration of action potentials at 50 % and 90 % repolarization was dose-dependently shortened in ziprasidone-treated LA. Diastolic tension in LA increased after ziprasidone treatment. Ziprasidone-treated LA showed rapid atrial pacing (RAP) triggered activity. PI3K inhibitor, Akt inhibitor and mTOR inhibitor abolished the triggered activity elicited by ziprasidone in LA. The NLRP3 inhibitor MCC950 suppressed the ziprasidone-induced post-RAP-triggered activity. MCC950 treatment reduced the reverse-mode Na+/Ca2+ exchanger current in ziprasidone-treated myocytes. Cytosolic reactive oxygen species production decreased in ziprasidone-treated atrial myocytes after MCC950 treatment. Protein levels of inflammasomes and proinflammatory cytokines, including NLRP3, caspase-1, IL-1β, IL-18, and IL-6 were observed to be upregulated in myocytes treated with ziprasidone. ConclusionsOur findings suggest ziprasidone induces atrial arrhythmia, potentially through upregulation of the NLRP3 inflammasome and enhancement of reactive oxygen species production via the PI3K/Akt/mTOR pathway.

Inhibitory effect of aloperine on transient outward potassium currents in rat cardiac myocytes.

Aloperine (ALO) is an effective quinolizidine alkaloid. Previous research has demonstrated its antiarrhythmic effect by inhibiting voltage-gated sodium currents in rat ventricular myocytes. This study explored its effect on transient outward potassium currents (Ito) in rat atrial myocytes to identify potential targets in the context of ion channel currents. The Ito characteristics in rat atrial myocytes were recorded using a whole-cell patch-clamp technique. Molecular docking was performed to validate ligand-protein binding interactions. ALO at concentrations of 3 and 10μM significantly reduced Ito current densities. Gating kinetics analysis revealed ALO's ability to slow Ito activation, hasten inactivation, and prolong transition from inactive to resting state. Molecular docking revealed that ALO could stably bind to KCND2. ALO may inhibit Ito by slowing the activation process, accelerating inactivation, and delaying the recovery time after inactivation, potentially preventing acetylcholine-induced AF.

Complex waveform of the calcium-activated TRPM4 ion channel current

Complex waveform of the calcium-activated TRPM4 ion channel current

Expression of model ion channel currents generated using neuron in silico software in real time using dynamic clamp

Expression of model ion channel currents generated using neuron in silico software in real time using dynamic clamp

Steady-state Approximations for Hodgkin-Huxley Cell Models: Towards Multi-scale Models of Uterine Smooth Muscle

The Tong, et al. 2011 publication presents a comprehensive mathematical model of electro- mechanical behaviour in a uterine smooth muscle cell. It incorporates ion channel currents into a classic Hodgkin-Huxley membrane voltage formulation as well as Ca2+ concentration dynamics with pumps and exchangers. Mechanical force generation by way of the Hai-Murphy smooth muscle cell model is computed based on the Ca2+ concentrations. The ‘full’ Tong, 2011 model (FTM) includes nineteen ordinary differential equations for the ion channel activation/inactivation variables out of a total of 105 equations overall. An effort at reducing the FTM into a smaller number of equations for computational efficiency – the ‘reduced’ Tong model (RTM) – aims at reproducing the overall behaviour of the FTM without excessive detail. We present here the CellML implementation of the RTM for simulating the FTM within the context of the reduced model’s primary publication as derived from the Tong, et al. 2011 model.

Steady-state Approximations for Hodgkin-Huxley Cell Models: Towards Multi-scale Models of Uterine Smooth Muscle

The Tong, et al. 2011 publication presents a comprehensive mathematical model of electro- mechanical behaviour in a uterine smooth muscle cell. It incorporates ion channel currents into a classic Hodgkin-Huxley membrane voltage formulation as well as Ca2+ concentration dynamics with pumps and exchangers. Mechanical force generation by way of the Hai-Murphy smooth muscle cell model is computed based on the Ca2+ concentrations. The ‘full’ Tong, 2011 model (FTM) includes nineteen ordinary differential equations for the ion channel activation/inactivation variables out of a total of 105 equations overall. An effort at reducing the FTM into a smaller number of equations for computational efficiency – the ‘reduced’ Tong model (RTM) – aims at reproducing the overall behaviour of the FTM without excessive detail. We present here the CellML implementation of the RTM for simulating the FTM within the context of the reduced model’s primary publication as derived from the Tong, et al. 2011 model.

CCK-8 enhances acid-sensing ion channel currents in rat primary sensory neurons

Cholecystokinin (CCK) is a peptide that has been implicated in pain modulation. Acid sensitive ion channels (ASICs) also play an important role in pain associated with tissue acidification. However, it is still unclear whether there is an interaction between CCK signaling and ASICs during pain process. Herein, we report that a functional link between them in rat dorsal root ganglion (DRG) neurons. Pretreatment with CCK-8 concentration-dependently increased acid-evoked ASIC currents. CCK-8 increased the maximum response of ASICs to acid, but did not changed their acid sensitivity. Enhancement of ASIC currents by CCK-8 was mediated by the stimulation of CCK2 receptor (CCK2R), rather than CCK1R. The enhancement of ASIC currents by CCK-8 was prevented by application of either G-protein inhibitor GDP-β-S or protein kinase C (PKC) inhibitor GF109203×, but not by protein kinase A (PKA) inhibitor H-89 or JNK inhibitor SP600125. Moreover, CCK-8 increased the number of action potentials triggered by acid stimuli by activating CCK2R. Finally, CCK-8 dose-dependently exacerbated acid-induced nociceptive behavior in rats through local CCK2R. Together, these results indicated that CCK-8/CCK2R activation enhanced ASIC-mediated electrophysiological activity in DRG neurons and nociception in rats. The enhancement effect depended on G-proteins and intracellular PKC signaling rather than PKA and JNK signaling pathway. These findings provided that CCK-8/CCK2R is an important therapeutic target for ASIC-mediated pain.

Pharmacological profiles and anti-inflammatory activity of pCN-diEPP and mCN-diEPP, new alpha9alpha10 nicotinic receptor ligands

Pain due to inflammation can be reduced by targeting the noncanonical nicotinic receptors (NCNR) in cells of the immune system that regulate the synthesis and release of pro- and anti-inflammatory cytokines. Although NCNR do not generate ion channel currents, the pharmacology of ion-channel forms of the receptors can predict drugs which may be effective regulators of the cholinergic anti-inflammatory system (CAS). Agonists of α7 type receptors have been definitively associated with CAS. Receptors containing α9 and α10 subunits have also been implicated. We have recently characterized two small molecules, pCN-diEPP and mCN-diEPP, as selective α9α10 agonists and antagonists, respectively. We used these drugs, along with nicotine, an α7 agonist and α9α10 antagonist, to probe the mixed populations of receptors that are formed when α7, α9, and α10 are all expressed together in Xenopus oocytes. We also evaluated the effects of the CN-diEPP compounds on regulating the ATP-induced release of interleukin-1β from monocytic THP-1 cells, which express NCNR. The compounds successfully identified separate populations of receptors when all three subunits were co-expressed, including a potential population of homomeric α10 receptors. The α9α10 agonist pCN-diEPP was the more effective regulator of interleukin-1β release in THP-1 cells. pCN-diEPP was also fully effective in a mouse model of inflammatory pain, while mCN-diEPP had only partial effects, requiring a higher dosage. The analgetic effects of pCN-diEPP and mCN-diEPP were retained in α7 knockout mice. Taken together, our results suggest that drugs that selectively activate α9α10 receptors may useful to reduce inflammatory pain through the CAS.

Neural energy computations based on Hodgkin-Huxley models bridge abnormal neuronal activities and energy consumption patterns of major depressive disorder

Limited by the current experimental techniques and neurodynamical models, the dysregulation mechanisms of decision-making related neural circuits in major depressive disorder (MDD) are still not clear. In this paper, we proposed a neural coding methodology using energy to further investigate it, which has been proven to strongly complement the neurodynamical methodology. We augmented the previous neural energy calculation method, and applied it to our VTA-NAc-mPFC neurodynamical H–H models. We particularly focused on the peak power and energy consumption of abnormal ion channel (ionic) currents under different concentrations of dopamine input, and investigated the abnormal energy consumption patterns for the MDD group. The results revealed that the energy consumption of medium spiny neurons (MSNs) in the NAc region were lower in the MDD group than that of the normal control group despite having the same firing frequencies, peak action potentials, and average membrane potentials in both groups. Dopamine concentration was also positively correlated with the energy consumption of the pyramidal neurons, but the patterns of different interneuron types were distinct. Additionally, the ratio of mPFC's energy consumption to total energy consumption of the whole network in MDD group was lower than that in normal control group, revealing that the mPFC region in MDD group encoded less neural information, which matched the energy consumption patterns of BOLD-fMRI results. It was also in line with the behavioral characteristics that MDD patients demonstrated in the form of reward insensitivity during decision-making tasks. In conclusion, the model in this paper was the first neural network energy computational model for MDD, which showed success in explaining its dynamical mechanisms with an energy consumption perspective. To build on this, we demonstrated that energy consumption levels can be used as a potential indicator for MDD, which also showed a promising pipeline to use an energy methodology for studying other neuropsychiatric disorders.

Naringin exerts antiarrhythmic effects by inhibiting channel currents in mouse cardiomyocytes.

Naringin, a flavonoid extracted from citrus plants, has a variety of biological effects. Studies have shown that increasing the consumption of flavonoid-rich foods can reduce the incidence of cardiac arrhythmia. Naringin has been reported to have beneficial cardiovascular effects and thus can be used to prevent cardiovascular diseases, but the electrophysiological mechanism through which it prevents arrhythmias has not been elucidated. This study was conducted to investigate the effect of naringin on the transmembrane ion channel currents in mouse ventricular myocytes and the antiarrhythmic effect of this compound on Langendorff-perfused mouse hearts. Action potentials (APs) and ionic currents were recorded in isolated ventricular myocytes using the whole-cell patch-clamp technique. Anemone toxin II (ATX II) and CaCl2 were used to induce early afterdepolarizations (EADs) and delayed afterdepolarizations (DADs), respectively. Electrocardiogram (ECG) recordings were conducted in Langendorff-perfused mouse hearts with a BL-420F biological signal acquisition and analysis system. At the cellular level, naringin shortened the action potential duration (APD) of ventricular myocytes and decreased the maximum depolarization velocity (Vmax) of APs.Naringin inhibited the L-type calcium current (ICa.L) and ATX II enhanced the late sodium current (INa.L) in a concentration-dependent manner with IC50 values of 508.5μmol/L (n=9) and 311.6μmol/L (n=10), respectively. In addition, naringin also inhibited the peak sodium current (INa·P) and delayed the rectifier potassium current (IK) and the transient outward potassium current (Ito). Moreover, naringin reduced ATX II-induced APD prolongation and EADs and had a significant inhibitory effect on CaCl2-induced DADs as well. At the organ level, naringin reduced the incidence of ventricular tachycardia (VT) and ventricular fibrillation (VF) induced by ATX II and shortened the duration of both in isolated hearts. Naringin can inhibit the occurrence of EADs and DADs at the cellular level; furthermore, it can inhibit INa.L, ICa.L, INa·P, IK, and Ito in ventricular myocytes. Naringin also inhibits arrhythmias induced by ATX II in hearts. By investigating naringin with this electrophysiological method for the first time, we determined that this flavonoid may be a multichannel blocker with antiarrhythmic effects.

Model-free idealization: Adaptive integrated approach for idealization of ion-channel currents

Single-channel electrophysiological recordings provide insights into transmembrane ion permeation and channel gating mechanisms. The first step in the analysis of the recorded currents involves an "idealization" process, in which noisy raw data are classified into two discrete levels corresponding to the open and closed states of channels. This provides valuable information on the gating kinetics of ion channels. However, the idealization step is often challenging in cases of currents with poor signal-to-noise ratios and baseline drifts, especially when the gating model of the target channel is not identified. We report herein on a highly robust model-free idealization method for achieving this goal. The algorithm, called adaptive integrated approach for idealization of ion-channel currents (AI2), is composed of Kalman filter and Gaussian mixture model clustering and functions without user input. AI2 automatically determines the noise reduction setting based on the degree of separation between the open and closed levels. We validated the method on pseudo-channel-current datasets that contain either computed or experimentally recorded noise. We also investigated the relationship between the noise reduction parameter of the Kalman filter and the cutoff frequency of the low-pass filter. The AI2 algorithm was then tested on actual experimental data for biological channels including gramicidin A, a voltage-gated sodium channel, and other unidentified channels. We compared the idealization results with those obtained by the conventional methods, including the 50%-threshold-crossing method.

Abstract P1037: Dysfunction Of N-terminal Acetylation Causes Multiple Electrical Abnormalities Leading To Long QT Syndrome And Dilated Cardiomyopathy

Introduction: NAA10-related syndrome is characterized by long QT syndrome (LQTS), cardiomyopathy, hypotonia, and neurodevelopmental delay. NAA10 complexes with the regulatory subunit NAA15 to make the post-translationally modifying N-terminal acetyltransferase, NatA. Despite the association of LQTS and NAA10 mutations, the mechanism is unknown. Hypothesis: NAA10 dysfunction affects the function of cardiac ion channels or related proteins causing LQTS, and sarcomere abnormalities causing cardiomyopathy. Methods: Target sequencing of large kindred with multiple family members who had LQTS and sudden death revealed a segregating mutation in NAA10 (c.10C>A; p.R4S). Somatic cell reprogramming was used to create an induced pluripotent stem cell (iPSC) line from a gene-positive male patient with LQTS and dilated cardiomyopathy (pNAA10 R4S ). Genome-editing was used to create the control iPSC line (eNAA10 R4S ). iPSC lines were differentiated into cardiomyocytes (iPSC-CMs) for further analysis. In addition, we performed biochemical assays to investigate the enzymatic activities of the NAA10-R4S mutation. Results: The NAA10-R4S mutation had reduced enzymatic activity, decreased expression levels of NAA10/NAA15 and destabilized the NatA complex. Action potential duration was prolonged in pNAA10 R4S - and eNAA10 R4S -iPSC-CMs as compared to WT iPSC-CMs (498.9 ± 38.8 ms and 514.1 ± 52.9 ms, vs 316.7 ± 48.2 ms; p<0.05). Investigation of the underlying ion channel currents revealed increased late I Na (Late I Na / Peak I Na : pNAA10 R4S : 0.062 ± 0.010 % and eNAA10 R4S : 0.074 ± 0.020 % vs. WT: 0.026 ± 0.005 %; p<0.05) and reduced I Ks (pNAA10 R4S : 0.18 ± 0.05 pA/pF and eNAA10 R4S : 0.26 ± 0.04 pA/pF vs. WT: 0.61 ± 0.15 pA/pF; p<0.05). There were no significant differences in I Kr and I CaL . Diastolic Ca 2+ levels were increased in mutant iPSC-CMs (F340/F380: 0.18 ± 0.02 vs 0.04 ± 0.01; p<0.05) consistent with impaired Ca 2+ handling. Plating iPSC-CMs on micro-contact printed islands revealed alterations in sarcomeric structure. Conclusion: We demonstrate that the NAA10 mutation cause abnormalities in ion channels and sarcomere development. Our data indicated a novel role for N-terminal acetylation in cardiac ion channel regulation leading to cardiovascular disorders.

Mechanisms of Atrial Fibrillation in Obstructive Sleep Apnoea.

Obstructive sleep apnoea (OSA) is a strong independent risk factor for atrial fibrillation (AF). Emerging clinical data cite adverse effects of OSA on AF induction, maintenance, disease severity, and responsiveness to treatment. Prevention using continuous positive airway pressure (CPAP) is effective in some groups but is limited by its poor compliance. Thus, an improved understanding of the underlying arrhythmogenic mechanisms will facilitate the development of novel therapies and/or better selection of those currently available to complement CPAP in alleviating the burden of AF in OSA. Arrhythmogenesis in OSA is a multifactorial process characterised by a combination of acute atrial stimulation on a background of chronic electrical, structural, and autonomic remodelling. Chronic intermittent hypoxia (CIH), a key feature of OSA, is associated with long-term adaptive changes in myocyte ion channel currents, sensitising the atria to episodic bursts of autonomic reflex activity. CIH is also a potent driver of inflammatory and hypoxic stress, leading to fibrosis, connexin downregulation, and conduction slowing. Atrial stretch is brought about by negative thoracic pressure (NTP) swings during apnoea, promoting further chronic structural remodelling, as well as acutely dysregulating calcium handling and electrical function. Here, we provide an up-to-date review of these topical mechanistic insights and their roles in arrhythmia.

#2696 IN SILICO ELECTROPHYSIOLOGICAL STUDY REVEALS TAMSULOSIN MEDIATE URETER SMOOTH MUSCLE CONTRACTION BY INCREASING POTASSIUM CURRENT

Abstract Background and Aims Tamsulosin is a common α1-AR antagonist that is prescribed to patients with acute kidney stone episodes [Scotland et al., 2021]. According to accumulated experimental data, abnormal peristaltic contraction of the ureter smooth muscle (USM) causes acute kidney stone episodes [Lang et al., 2006]. Intracellular electrical activities like membrane depolarization and action potentials play important roles in modulating the USM contraction by releasing intracellular calcium from the sarcoplasmic reticulum. Therefore, an electrophysiological study will be helpful to assess the USM cell's electrical activities and in diagnosing abnormal USM contraction. Transient potassium channels (KA) are prevalent in different systems and hold immense importance for maintaining/performing selective electrophysiological functions. The present study investigates the altered electrophysiological characteristics of the USM cell because of the induction of Tamsulosin doses. Method The single isolated USM cell comprises several voltage-gated ion channels, such as two voltage-gated calcium (T-type, and L-type) channels, one voltage-gated fast potassium (KA) channel, one calcium-dependent large conductance potassium channel, and an HCN channel. The individual ion channel currents and the membrane potential are recorded by utilizing both the voltage clamp and current clamp protocols. A Tamsulosin drug (0.5 mg) model for the KA channel is introduced by multiplying the maximal conductance of the KA channel with a scaling factor between 0 and 1 to mimic the drug concentration. Statistical analysis protocols are evaluated for analytical purposes. Results In this in silico electrophysiological model, the resting membrane potential is maintained at −75 mV, as this value is cited by various experimental studies. The ionic concentrations and biophysical parameters for all ion channels are varied in the physiological ranges. Under the voltage clamp protocol, the voltage steps are increased from a holding potential of −80 mV to −10 mV with a 10 mV of step voltage. In Figure 1, the red and blue solid lines represent recorded outward KA current from the isolated USM cell under both control and applied Tamsulosin dose conditions. Figure 1 reveals that the KA current is elevated after the application of the Tamsulosin drug regarding all step voltages. As a result, the total outward current is elevated and the USM action potential duration is shortened. It is also observed that the steady-state activation curve of the KA channel is shifted to more negative after applying Tamsulosin. The USM cell is electrically less excitable with the Tamsulosin. Conclusion This first in-silico study reveals the KA ionic current, which plays a major role in coordinating ureteral contractions, is altered due to Tamsulosin. It implies that the pharmacological maneuver of Tamsulosin is substantially beneficial to treat dysfunctional peristalsis by reducing the symptoms and installation complexities from the ureteral stents procedure.