Search Results (38)

The “athlete’s heart” phenotype, featuring resting bradycardia, has traditionally been viewed as a benign adaptation. However, emerging evidence associates prolonged, high-intensity endurance training with an increased risk of clinical sinoatrial node dysfunction. This systematic review synthesizes evidence on exercise-induced intrinsic Sinoatrial Node (SAN) electrophysiological remodelling and evaluates its dual nature along the adaptation–pathology continuum. Following PRISMA guidelines, a systematic search of PubMed, Web of Science, and Google Scholar (2000–2025) identified 17 eligible studies. Analysis revealed that in humans, rodents, and rabbits, exercise induces intrinsic SAN electrophysiological remodelling—a “membrane clock” reset characterized by coordinated downregulation of pacemaker currents, notably Hyperpolarization-activated cyclic nucleotide-gated cation channel (I_f), via the Nkx2.5-miR-423-5p transcription factor pathway. Evidence for “calcium clock” involvement remains inconsistent. In contrast, large animal models (e.g., dogs, horses) show only parasympathetic-mediated bradycardia without intrinsic remodelling. Training loads may induce structural changes (e.g., fibrosis), providing an anatomical substrate for pathology. Moderating factors such as training type and ageing contribute to a phenotype of “acquired SAN reserve reduction. Exercise-induced intrinsic SAN remodelling is a physiological adaptation mechanism that, under certain conditions, can cross a threshold to become a pathological cause of clinical dysfunction. Recognizing this continuum is essential for risk stratification and future therapeutic innovation. Full article

QX-314 is a positively charged lidocaine derivative with the membrane-impermeant property. This compound applied at the intracellular side has been shown to suppress the voltage-gated Na⁺ current (I_Na), while lidocaine itself acts to suppress the hyperpolarization-activated cation current (I_h). To what extent this drug may exert any effects on various plasmalemmal ionic currents still remains largely unknown. This investigation focused on the impact of QX-314 on ionic currents in GH₃ cells derived from pituitary tumors. This compound applied extracellularly was noted to differentially suppress the amplitude of transient and late I_Na with an IC₅₀ value of 93 and 42 μM, respectively. In GH₃ cells dialyzed with QX-314 (10 μM), the I_Na(T) amplitude evoked by a brief depolarizing step was decreased, and its inactivation was increased. Moreover, QX-314, when applied extracellularly at 100 μM, diminished the amplitude of the I_h current with an IC₅₀ of 68 μM. Intracellular dialysis with QX-314 also suppressed I_h amplitude; moreover, the later application of oxaliplatin reversed this suppression. As cells were extracellularly and continually exposed to QX-314, the magnitude of the erg-mediated K⁺ current (I_K(erg)) was also effectively suppressed with an IC₅₀ value of 73 μM. Furthermore, upon intracellular dialysis with QX-314 (10 μM), the degree of the voltage-dependent hysteresis (Hys_(V)) of I_K(erg) during the long-lasting isosceles-triangular ramp voltage was decreased; during continued exposure to QX-314, further extracellular bath additions of PD118057 (10 μM) counteracted QX-314-induced suppression. However, the extracellular addition of QX-314 (100 μM) mildly suppressed the outward delayed rectifier K⁺ current in GH₃ cells. Collectively, QX-314 effectively suppressed I_Na, I_h, and I_K(erg) in GH₃ cells, a model of endocrine function, and these actions may contribute to their physiological functions, if similar effects are observed in vivo. Full article

The GABA_A receptors, through a short-term interaction with a mediator, induce hyperpolarization of the membrane potential (V_m) via the passive influx of chloride ions (Cl⁻) into neurons. The massive (or intense) activation of the GABA_ARs by the agonist could potentially lead to depolarization/excitation of the V_m. Although the ionic mechanisms of GABA_A-mediated depolarization remain incompletely understood, a combination of the outward chloride current and the inward bicarbonate current and the resulting pH shift are the main reasons for this event. The GABA_A responses are determined by the ionic gradients—neuronal pH/bicarbonate homeostasis is maintained by carbonic anhydrase and electroneutral/electrogenic bicarbonate transporters and the chloride level is maintained by secondary active cation–chloride cotransporters. Massive activation can also induce the rundown effect of the receptor function. This rundown effect partly involves phosphorylation, Ca²⁺ and the processes of receptor desensitization. In addition, by various methods (including fluorescence and optical genetic methods), it has been shown that massive activation of GABA_ARs during pathophysiological activity is also associated with an increase in [Cl⁻]_i and a decline in the pH and ATP levels in neurons. Although the relationship between the neuronal changes induced by massive activation of GABAergic signaling and the risk of developing neurodegenerative disease has been extensively studied, the molecular determinants of this process remain somewhat mysterious. The aim of this review is to summarize the data on the relationship between the massive activation of inhibitory signaling and the ionic changes in neurons. The potential role of receptor dysfunction during massive activation and the resulting ionic and metabolic disruption in neurons during the manifestation of network/seizure activity will be considered. Full article

Pituitary cells are specialized cells located within the pituitary gland, a small, pea-sized gland situated at the base of the brain. Through the use of cellular electrophysiological techniques, the electrical properties of these cells have been revealed. This review paper aims to introduce the ion currents that are known to be functionally expressed in pituitary cells. These currents include a voltage-gated Na⁺ current (I_Na), erg-mediated K⁺ current (I_K(erg)), M-type K⁺ current (I_K(M)), hyperpolarization-activated cation current (I_h), and large-conductance Ca²⁺-activated K⁺ (BK_Ca) channel. The biophysical characteristics of the respective ion current were described. Additionally, we also provide explanations for the effect of various drugs or compounds on each of these currents. GH₃-cell exposure to GV-58 can increase the magnitude of I_Na with a concurrent rise in the inactivation time constant of the current. The presence of esaxerenone, an antagonist of the aldosterone receptor, directly suppresses the magnitude of peak and late I_Na. Risperidone, an atypical antipsychotic agent, is effective at suppressing the I_K(erg) amplitude directly, and di(2-ethylhexyl)-phthalate suppressed I_K(erg). Solifenacin and kynurenic acid can interact with the K_M channel to stimulate I_K(M), while carisbamate and cannabidiol inhibit the I_h amplitude activated by sustained hyperpolarization. Moreover, the presence of either rufinamide or QO-40 can enhance the activity of single BK_Ca channels. To summarize, alterations in ion currents within native pituitary cells or pituitary tumor cells can influence their functional activity, particularly in processes like stimulus–secretion coupling. The effects of small-molecule modulators, as demonstrated here, bear significance in clinical, therapeutic, and toxicological contexts. Full article

Background: Small conductance Ca²⁺ activated K⁺ channels (K_Ca2.3) are important regulators of vascular function. They provide Ca²⁺-dependent hyperpolarization of the endothelial membrane potential, promoting agonist-induced vasodilation. Another important mechanism of influence may occur through positive feedback regulation of endothelial Ca²⁺ signals, likely via amplification of influx through membrane cation channels. K_Ca2.3 channels have recently been implicated in flow-mediated dilation of the arterial vasculature and may contribute to the crucial homeostatic role of shear stress in preventing vascular wall remodeling and progressive vascular disease (i.e., atherosclerosis). The impact of K_Ca2.3 channels on endothelial Ca²⁺ signaling under physiologically relevant shear stress conditions remains unknown. Methods: In the current study, we employ mice expressing an endothelium-specific Ca²⁺ fluorophore (cdh5-GCaMP8) to characterize the K_Ca2.3 channel influence on the dynamic Ca²⁺ signaling profile along the arterial endothelium in the presence and absence of shear-stress. Results: Our data indicate K_Ca2.3 channels have a minimal influence on basal Ca²⁺ signaling in the carotid artery endothelium in the absence of flow, but they contribute substantially to amplification of Ca²⁺ dynamics in the presence of flow and their influence can be augmented through exogenous positive modulation. Conclusions: The findings suggest a pivotal role for K_Ca2.3 channels in adjusting the profile of homeostatic dynamic Ca²⁺ signals along the arterial intima under flow. Full article

In vitro experiments performed on dissociated dorsal root ganglion (DRG) neurons suggest the involvement of the hyperpolarization-activated cation current (I_h) in enhancing neuronal excitability, potentially contributing to neuropathic pain. However, the more confirmative in vivo information about how nerve injury interacts with I_h is lacking. In this study, I_h was recorded in vivo using the dynamic single-electrode voltage clamp (dSEVC) technique on L5 DRG neurons of normal rats and those seven days after spinal nerve axotomy (SNA). Compared to normal rats, SNA unexpectedly inhibited the activity of I_h channels on A-fiber DRG neurons: (a) the I_h current magnitude, density, and conductance were consistently diminished; and (b) the I_h activation velocity was slowed and the voltage for I_h activation was hyperpolarized. The half-activation voltage (V_0.5) exhibited a negative shift, and the time constant for I_h activation was prolonged across all test potentials, indicating the reduced availability of I_h after SNA. To further investigate the mechanisms of SNA on I_h, the underlying HCN channels and the correlated mRNA were quantified and compared. The mRNA expression level of HCN1-4 was uniformly enhanced after SNA, which might have contributed to the increased cytoplasmic HCN1 intensity observed in both medium- and large-sized DRG neurons. This finding contradicted the functional reduction of I_h after SNA. Surprisingly, the HCN labeling pattern was altered after SNA: the labeling area of HCN1 and HCN2 at the membranous ring region of the axotomized large neurons became significantly thinner or absent. We concluded that the diminished ring immunoreactivity for HCN1 and HCN2 correlated with a reduced availability of I_h channels, elucidating the observed decrease in I_h in axotomized A-fiber neurons. Full article

Cannabidiol (CBD) is a naturally occurring compound found in the Cannabis plant that is known for its potential therapeutic effects. However, its impact on membrane ionic currents remains a topic of debate. This study aimed to investigate how CBD modifies various types of ionic currents in pituitary GH₃ cells. Results showed that exposure to CBD led to a concentration-dependent decrease in M-type K⁺ currents (I_K(M)), with an IC₅₀ of 3.6 μM, and caused the quasi-steady-state activation curve of the current to shift to a more depolarized potential with no changes in the curve’s steepness. The CBD-mediated block of I_K(M) was not reversed by naloxone, suggesting that it was not mediated by opioid receptors. The I_K(M) elicited by pulse-train stimulation was also decreased upon exposure to CBD. The magnitude of erg-mediated K⁺ currents was slightly reduced by adding CBD (10 μM), while the density of voltage-gated Na⁺ currents elicited by a short depolarizing pulse was not affected by it. Additionally, CBD decreased the magnitude of hyperpolarization-activated cation currents (I_h) with an IC₅₀ of 3.3 μM, and the decrease was reversed by oxaliplatin. The quasi-steady-state activation curve of I_h was shifted in the leftward direction with no changes in the slope factor of the curve. CBD also diminished the strength of voltage-dependent hysteresis on I_h elicited by upright isosceles-triangular ramp voltage. Collectively, these findings suggest that CBD’s modification of ionic currents presented herein is independent of cannabinoid or opioid receptors and may exert a significant impact on the functional activities of excitable cells occurring in vitro or in vivo. Full article

The hyperpolarization-activated cation current (I_h) exhibits a slowly activating time course of the current (I_h) when the cell membrane is hyperpolarized for an extended duration. It is involved in generating electrical activity in various excitable cells. Numerous structurally distinct compounds or herbal drugs have the potential to impact both the magnitude and gating kinetics of this current. Brivaracetam, a chemical analog of levetiracetam known to be a ligand for synaptic vesicle protein 2A, could directly suppress the I_h magnitude. Carisbamate, an anticonvulsant agent, not only inhibited the I_h amplitude but also reduced the strength of voltage-dependent hysteresis (Hys_(V)) associated with I_h. Cilobradine, similar to ivabradine, inhibited the amplitude of I_h; however, it also suppressed the amplitude of delayed-rectifier K⁺ currents. Dexmedetomidine, an agonist of α2-adrenergic receptor, exerted a depressant action on I_h in a concentration-dependent fashion. Suppression of I_h amplitude was observed when GAL-021, a breathing control modulator, was present at a concentration exceeding 30 μM. Lutein, one of the few xanthophyll carotenoids, was able to suppress the I_h amplitude as well as to depress Hys_(V)’s strength of I_h. Pirfenidone, a pyridine derivative known to be an anti-fibrotic agent, depressed the I_h magnitude in a concentration- and voltage-dependent fashion. Tramadol, a synthetic centrally active analgesic, was shown to reduce the I_h magnitude, independent of its interaction with opioid receptors. Various herbal drugs, including ent-kaurane-type diterpenoids from Croton tonkinensis, Ganoderma triterpenoids, honokiol, and pterostilbene, demonstrated efficacy in reducing the magnitude of I_h. Conversely, oxaliplatin, a platinum-based chemotherapeutic compound, was observed to effectively increase the I_h amplitude. Collectively, the regulatory effects of these compounds or herbal drugs on cellular function can be partly attributed to their perturbations on I_h. Full article

The visual process begins with the absorption of photons by photopigments of cone and rod photoreceptors in the retina. In this process, the signal is first amplified by a cyclic guanosine monophosphate (cGMP)-based signaling cascade and then converted into an electrical signal by cyclic nucleotide-gated (CNG) channels. CNG channels are purely ligand-gated channels whose activity can be controlled by cGMP, which induces a depolarizing Na⁺/Ca²⁺ current upon binding to the channel. Structurally, CNG channels belong to the superfamily of pore-loop cation channels and share structural similarities with hyperpolarization-activated cyclic nucleotide (HCN) and voltage-gated potassium (KCN) channels. Cone and rod photoreceptors express distinct CNG channels encoded by homologous genes. Mutations in the genes encoding the rod CNG channel (CNGA1 and CNGB1) result in retinitis-pigmentosa-type blindness. Mutations in the genes encoding the cone CNG channel (CNGA3 and CNGB3) lead to achromatopsia. Here, we review the molecular properties of CNG channels and describe their physiological and pathophysiological roles in the retina. Moreover, we summarize recent activities in the field of gene therapy aimed at developing the first gene therapies for CNG channelopathies. Full article

The non-linear voltage-dependent hysteresis (Hys_(V)) of voltage-gated ionic currents can be robustly activated by the isosceles-triangular ramp voltage (V_ramp) through digital-to-analog conversion. Perturbations on this Hys_(V) behavior play a role in regulating membrane excitability in different excitable cells. A variety of small molecules may influence the strength of Hys_(V) in different types of ionic currents elicited by long-lasting triangular V_ramp. Pirfenidone, an anti-fibrotic drug, decreased the magnitude of I_h’s Hys_(V) activated by triangular V_ramp, while dexmedetomidine, an agonist of α₂-adrenoceptors, effectively suppressed I_h as well as diminished the Hys_(V) strength of I_h. Oxaliplatin, a platinum-based anti-neoplastic drug, was noted to enhance the I_h’s Hys_(V) strength, which is thought to be linked to the occurrence of neuropathic pain, while honokiol, a hydroxylated biphenyl compound, decreased I_h’s Hys_(V). Cell exposure to lutein, a xanthophyll carotenoid, resulted in a reduction of I_h’s Hys_(V) magnitude. Moreover, with cell exposure to UCL-2077, SM-102, isoplumbagin, or plumbagin, the Hys_(V) strength of erg-mediated K⁺ current activated by triangular V_ramp was effectively diminished, whereas the presence of either remdesivir or QO-58 respectively decreased or increased Hys_(V) magnitude of M-type K⁺ current. Zingerone, a methoxyphenol, was found to attenuate Hys_(V) (with low- and high-threshold loops) of L-type Ca²⁺ current induced by long-lasting triangular V_ramp. The Hys_(V) properties of persistent Na⁺ current (I_Na(P)) evoked by triangular V_ramp were characterized by a figure-of-eight (i.e., ∞) configuration with two distinct loops (i.e., low- and high-threshold loops). The presence of either tefluthrin, a pyrethroid insecticide, or t-butyl hydroperoxide, an oxidant, enhanced the Hys_(V) strength of I_Na(P). However, further addition of dapagliflozin can reverse their augmenting effects in the Hys_(V) magnitude of the current. Furthermore, the addition of esaxerenone, mirogabalin, or dapagliflozin was effective in inhibiting the strength of I_Na(P). Taken together, the observed perturbations by these small-molecule modulators on Hys_(V) strength in different types of ionic currents evoked during triangular V_ramp are expected to influence the functional activities (e.g., electrical behaviors) of different excitable cells in vitro or in vivo. Full article

Ubiquinone, composed of a 1,4-benzoquinone and naturally produced in the body, actively participates in the mitochondrial redox reaction and functions as an endogenous lipid antioxidant, protecting against peroxidation in the pituitary-dependent hormonal system. However, the questions of if and how ubiquinone directly affects neuronal ionic currents remain largely unsettled. We investigated its effects on ionic currents in pituitary neurons (GH3 and MMQ cells) with the aid of patch-clamp technology. Ubiquinone decreased the peak amplitude of the voltage-gated Na⁺ current (I_Na) with a slowing of the inactivation rate. Neither menadione nor superoxide dismutase modified the ubiquinone-induced I_Na inhibition. In response to an isosceles-triangular ramp pulse, the persistent I_Na (I_Na(P)) at high- and low- threshold potentials occurred concurrently with a figure-eight hysteresis loop. With ubiquinone, the I_Na(P) increased with no change in the intersection voltage, and the magnitude of the voltage-dependent hysteresis of the current was enhanced. Ubiquinone was ineffective in modifying the gating of hyperpolarization-activated cation currents. In MMQ lactotrophs, ubiquinone effectively decreased the amplitude of the I_Na and the current inactivation rate. In sum, the effects of ubiquinone demonstrated herein occur upstream of its effects on mitochondrial redox processes, involved in its modulation of sodium channels and neuronal excitability. Full article

Lutein (β,ε-carotene-3,3′-diol), a xanthophyll carotenoid, is found in high concentrations in the macula of the human retina. It has been recognized to exert potential effectiveness in antioxidative and anti-inflammatory properties. However, whether and how its modifications on varying types of plasmalemmal ionic currents occur in electrically excitable cells remain incompletely answered. The current hypothesis is that lutein produces any direct adjustments on ionic currents (e.g., hyperpolarization-activated cation current, I_h [or funny current, I_f]). In the present study, GH₃-cell exposure to lutein resulted in a time-, state- and concentration-dependent reduction in I_h amplitude with an IC₅₀ value of 4.1 μM. There was a hyperpolarizing shift along the voltage axis in the steady-state activation curve of I_h in the presence of this compound, despite being void of changes in the gating charge of the curve. Under continued exposure to lutein (3 μM), further addition of oxaliplatin (10 μM) or ivabradine (3 μM) could be effective at either reversing or further decreasing lutein-induced suppression of hyperpolarization-evoked I_h, respectively. The voltage-dependent anti-clockwise hysteresis of I_h responding to long-lasting inverted isosceles-triangular ramp concentration-dependently became diminished by adding this compound. However, the addition of 10 μM lutein caused a mild but significant suppression in the amplitude of erg-mediated or A-type K⁺ currents. Under current-clamp potential recordings, the sag potential evoked by long-lasting hyperpolarizing current stimulus was reduced under cell exposure to lutein. Altogether, findings from the current observations enabled us to reflect that during cell exposure to lutein used at pharmacologically achievable concentrations, lutein-perturbed inhibition of I_h would be an ionic mechanism underlying its changes in membrane excitability. Full article

Multiple sclerosis (MS) is a demyelinating disease of the central nervous system that is characterized by the progressive loss of oligodendrocytes and myelin and is associated with thalamic dysfunction. Cuprizone (CPZ)-induced general demyelination in rodents is a valuable model for studying different aspects of MS pathology. CPZ feeding is associated with the altered distribution and expression of different ion channels along neuronal somata and axons. However, it is largely unknown whether the copper chelator CPZ directly influences ion channels. Therefore, we assessed the effects of different divalent cations (copper; zinc) and trace metal chelators (EDTA; Tricine; the water-soluble derivative of CPZ, BiMPi) on hyperpolarization-activated cyclic nucleotide-gated (HCN) channels that are major mediators of thalamic function and pathology. In addition, alterations of HCN channels induced by CPZ treatment and MS-related proinflammatory cytokines (IL-1β; IL-6; INF-α; INF-β) were characterized in C57Bl/6J mice. Thus, the hyperpolarization-activated inward current (I_h) was recorded in thalamocortical (TC) neurons and heterologous expression systems (mHCN2 expressing HEK cells; hHCN4 expressing oocytes). A number of electrophysiological characteristics of I_h (potential of half-maximal activation (V_0.5); current density; activation kinetics) were unchanged following the extracellular application of trace metals and divalent cation chelators to native neurons, cell cultures or oocytes. Mice were fed a diet containing 0.2% CPZ for 35 days, resulting in general demyelination in the brain. Withdrawal of CPZ from the diet resulted in rapid remyelination, the effects of which were assessed at three time points after stopping CPZ feeding (Day1, Day7, Day25). In TC neurons, I_h was decreased on Day1 and Day25 and revealed a transient increased availability on Day7. In addition, we challenged naive TC neurons with INF-α and IL-1β. It was found that I_h parameters were differentially altered by the application of the two cytokines to thalamic cells, while IL-1β increased the availability of HCN channels (depolarized V_0.5; increased current density) and the excitability of TC neurons (depolarized resting membrane potential (RMP); increased the number of action potentials (APs); produced a larger voltage sag; promoted higher input resistance; increased the number of burst spikes; hyperpolarized the AP threshold), INF-α mediated contrary effects. The effect of cytokine modulation on thalamic bursting was further assessed in horizontal slices and a computational model of slow thalamic oscillations. Here, IL-1β and INF-α increased and reduced oscillatory bursting, respectively. We conclude that HCN channels are not directly modulated by trace metals and divalent cation chelators but are subject to modulation by different MS-related cytokines. Full article

A number of distinct electrophysiological mechanisms that modulate the myogenic spontaneous pacemaker activity in the sinoatrial node (SAN) of the mammalian heart have been investigated extensively. There is agreement that several (3 or 4) different transmembrane ionic current changes (referred to as the voltage clock) are involved; and that the resulting net current interacts with direct and indirect effects of changes in intracellular Ca²⁺ (the calcium clock). However, significant uncertainties, and important knowledge gaps, remain concerning the functional roles in SAN spontaneous pacing of many of the individual ion channel- or exchanger-mediated transmembrane current changes. We report results from patch clamp studies and mathematical modeling of the hyperpolarization-activated current, I_f, in the generation/modulation of the diastolic depolarization, or pacemaker potential, produced by individual myocytes that were enzymatically isolated from the adult mouse sinoatrial node (SAN). Amphotericin-mediated patch microelectrode recordings at 35 °C were made under control conditions and in the presence of 5 or 10 nM isoproterenol (ISO). These sets of results were complemented and integrated with mathematical modeling of the current changes that take place in the range of membrane potentials (−70 to −50 mV), which corresponds to the ‘pacemaker depolarization’ in the adult mouse SAN. Our results reveal a very small, but functionally important, approximately steady-state or time-independent current generated by residual activation of I_f channels that are expressed in these pacemaker myocytes. Recordings of the pacemaker depolarization and action potential, combined with measurements of changes in I_f, and the well-known increases in the L-type Ca²⁺ current, I_CaL, demonstrated that I_CaL activation, is essential for myogenic pacing. Moreover, after being enhanced (approximately 3-fold) by 5 or 10 nM ISO, I_CaL contributes significantly to the positive chronotropic effect. Our mathematical model has been developed in an attempt to better understand the underlying mechanisms for the pacemaker depolarization and action potential in adult mouse SAN myocytes. After being updated with our new experimental data describing I_f, our simulations reveal a novel functional component of I_f in adult mouse SAN. Computational work carried out with this model also confirms that in the presence of ISO the residual activation of I_f and opening of I_CaL channels combine to generate a net current change during the slow diastolic depolarization phase that is essential for the observed accelerated pacemaking rate of these SAN myocytes. Full article

SM-102 (1-octylnonyl 8-[(2-hydroxyethyl)[6-oxo-6-(undecyloxy)hexyl]amino]-octanoate) is an amino cationic lipid that has been tailored for the formation of lipid nanoparticles and it is one of the essential ingredients present in the Moderna^TM COVID-19 vaccine. However, to what extent it may modify varying types of plasmalemmal ionic currents remains largely uncertain. In this study, we investigate the effects of SM-102 on ionic currents either in two types of endocrine cells (e.g., rat pituitary tumor (GH₃) cells and mouse Leydig tumor (MA-10) cells) or in microglial (BV2) cells. Hyperpolarization-activated K⁺ currents in these cells bathed in high-K⁺, Ca²⁺-free extracellular solution were examined to assess the effects of SM-102 on the amplitude and hysteresis of the erg-mediated K⁺ current (I_K(erg)). The SM-102 addition was effective at blocking I_K(erg) in a concentration-dependent fashion with a half-maximal concentration (IC₅₀) of 108 μM, a value which is similar to the K_D value (i.e., 134 μM) required for its accentuation of deactivation time constant of the current. The hysteretic strength of I_K(erg) in response to the long-lasting isosceles-triangular ramp pulse was effectively decreased in the presence of SM-102. Cell exposure to TurboFectin^TM 8.0 (0.1%, v/v), a transfection reagent, was able to inhibit hyperpolarization-activated I_K(erg) effectively with an increase in the deactivation time course of the current. Additionally, in GH₃ cells dialyzed with spermine (30 μM), the I_K(erg) amplitude progressively decreased; moreover, a further bath application of SM-102 (100 μM) or TurboFectin (0.1%) diminished the current magnitude further. In MA-10 Leydig cells, the I_K(erg) was also blocked by the presence of SM-102 or TurboFectin. The IC₅₀ value for SM-102-induced inhibition of I_K(erg) in MA-10 cells was 98 μM. In BV2 microglial cells, the amplitude of the inwardly rectifying K⁺ current was inhibited by SM-102. Taken together, the presence of SM-102 concentration-dependently inhibited I_K(erg) in endocrine cells (e.g., GH₃ or MA-10 cells), and such action may contribute to their functional activities, assuming that similar in vivo findings exist. Full article