K+ channel properties in cultured mouse Schwann cells: dependence on extracellular K+

In cultured Schwann cells, single-channel and whole-cell K+ currents can be activated by depolarizing the membrane to values more negative than -50 mV. In elevated extracellular K+ concentration ([K+]o), however, single-channel activity and whole-cell currents could be recorded at more negative potentials. Thus, the threshold of current activation was shifted to more negative potentials. This shift in the activation threshold was only observed with normal (50-60 mM) intracellular [K+] levels; it was not apparent when [K+]i was elevated to 145 mM. The control of [K+]o on the gating properties of K+ channels may serve to enhance the capability of the Schwann cell to take up [K+]o and thus may serve for [K+] homeostasis in the peripheral nerve.     

Redox properties of the adenoside triphosphate-sensitive K+ channel in brain mitochondria

Brain mitochondrial ATP-sensitive K+ channel (mitoK(ATP)) opening by diazoxide protects against ischemic damage and excitotoxic cell death. Here we studied the redox properties of brain mitoK(ATP) . MitoK(ATP) activation during excitotoxicity in cultured cerebellar granule neurons prevented the accumulation of reactive oxygen species (ROS) and cell death. Furthermore, mitoK(ATP) activation in isolated brain mitochondria significantly prevented H2O2 release by these organelles but did not change Ca2+ accumulation capacity. Interestingly, the activity of mitoK(ATP) was highly dependent on redox state. The thiol reductant mercaptopropionylglycine prevented mitoK(ATP) activity, whereas exogenous ROS activated the channel. In addition, the use of mitochondrial substrates that led to higher levels of endogenous mitochondrial ROS release closely correlated with enhanced K+ transport activity through mitoK(ATP). Altogether, our results indicate that brain mitoK(ATP) is a redox-sensitive channel that controls mitochondrial ROS release.     

The pattern of ATP‐sensitive K+ channel subunits,Kir6.2 and SUR1 mRNA expressions in DG region is different from those in CA1‐3 regions of chronic epilepsy induced by picrotoxin in rats

ATP‐sensitive K⁺ (K_ATP) channel's function is a key determinant of both excitability and viability of neurons. In the present report, in situ hybridization histochemistry and Western blot were used to examine whether picrotoxin (PTX)‐kindling convulsions involved the changes in distribution of K_ATP channels. The data demonstrated that the formation of kindling state was associated with a decreased amount of Kir6.2 mRNAs and proteins both in cerebral cortex and dentate gyrus (DG) as well as with a decreased amount of (regulatory subunit) SUR 1 mRNAs in DG. In contrast, resulting from a PTX re‐induced seizure insult, both subunits were transiently up‐modulated but not exactly paralleled between them and among different regions. In DG, Kir6.2 mRNAs increased toward normal levels at 12 h, followed a gradual decrease from 1 day to 3 days, being distinct from that detected in CA1‐3 regions in which no significant change was shown. Further, SUR1 mRNAs markedly increased at 12 h, decreased significantly at 1 day, and even went down to a faint level at 3 days which was similar to that of CA1‐3 regions, and there was no significant change in CA1‐3 regions of SUR1 mRNAs. Also, at 7 days after a PTX re‐treatment, Kir6.2 proteins increased significantly in the cortex, CA1, CA3 and DG (increasing 49.52%, 39.36%, 33.41%, and 54.79%, respectively) as well, SUR1 proteins increased significantly in DG (increasing 3.42 times), as compared with kindling rats without PTX retreatments (P < 0.05). These results indicated that K_ATP channels in brain particularly in DG are likely related to enhanced seizure susceptibility and dynamic controls of seizure propagation of chronic epilepsy induced by PTX in rats.     

Vastus lateralis NA+‐K+‐ATpase activity,protein, and isoform distribution in chronic obstructive pulmonary disease

In this study we investigate the hypothesis that protein abundance, isoform distribution, and maximal catalytic activity of sodium–potassium–adenosine triphosphatase (Na⁺‐K⁺‐ATPase) would be altered in muscle of patients with moderate to severe chronic obstructive pulmonary disease (COPD). Tissue samples were obtained from the vastus lateralis of 10 patients with COPD (mean ± SE: age = 67 ± 2.9 years; FEV₁ = 39 ± 5.5%) and 10 healthy, matched controls (CON: age = 68 ± 2 years; FEV₁ = 114 ± 4.2%). The samples were assessed for maximal catalytic activity (V_max) of the enzyme using the K⁺‐stimulated 3‐O‐methylfluorescein‐phosphatase (3‐O‐MFPase) assay, enzyme abundance using the [³H]‐ouabain assay, and isoform content of both α (α₁, α₂, α₃) and β (β₁, β₂, β₃) using Western blot techniques. A 19.4% lower (P < 0.05) V_max was observed in COPD compared with CON (90.7 ± 6.7 vs. 73.1 ± 4.7 nmol · mg protein^?1 h^?1). No differences between groups were observed for pump concentration (259 ± 15 vs. 243 ± 17 pmol · g wet weight). For the isoforms, α₁ was decreased by 28% (P < 0.05), and α₂ was increased by 12% (P < 0.05) in COPD compared with CON. No differences between groups were observed for α₃ or for the β isoforms. We conclude that moderate COPD compromises V_max, which occurs in the absence of changes in pump abundance. The reduction in V_max could be due to a shift in isoform expression (α₁, α₂), alterations in intrinsic regulation, or to structural changes in the enzyme. The changes observed in the catalytic activity of the pump could have major effects on membrane excitability and fatigability, which are typically compromised in COPD. Muscle Nerve, 2009     

The role of Na+‐K+‐ATPase in the epileptic brain

Na+‐K+‐ATPase, a P‐type ATP‐powered ion transporter on cell membrane, plays a vital role in cellular excitability. Cellular hyperexcitability, accompanied by hypersynchronous firing, is an important basis for seizures/epilepsy. An increasing number of studies point to a significant contribution of Na+‐K+‐ATPase to epilepsy, although discordant results exist. In this review, we comprehensively summarize the structure and physiological function of Na+‐K+‐ATPase in the central nervous system and critically evaluate the role of Na+‐K+‐ATPase in the epileptic brain. Importantly, we further provide perspectives on some possible research directions and discuss its potential as a therapeutic target for the treatment of epilepsy.     

3,4‐diaminopyridine base effectively treats the weakness of Lambert‐Eaton myasthenia

Introduction: 3,4‐diaminopyridine has been used to treat Lambert‐Eaton myasthenia (LEM) for 30 years despite the lack of conclusive evidence of efficacy. Methods: We conducted a randomized double‐blind placebo‐controlled withdrawal study in patients with LEM who had been on stable regimens of 3,4‐diaminopyridine base (3,4‐DAP) for ≥ 3 months. The primary efficacy endpoint was >30% deterioration in triple timed up‐and‐go (3TUG) times during tapered drug withdrawal. The secondary endpoint was self‐assessment of LEM–related weakness (W‐SAS). Results: Thirty‐two participants were randomized to continuous 3,4‐DAP or placebo groups. None of the 14 participants who received continuous 3,4‐DAP had > 30% deterioration in 3TUG time versus 72% of the 18 who tapered to placebo (P < 0.0001). W‐SAS similarly demonstrated an advantage for continuous treatment over placebo (P < 0.0001). Requirement for rescue and adverse events were more common in the placebo group. Discussion: This trial provides significant evidence of efficacy of 3,4‐DAP in the maintenance of strength in LEM. Muscle Nerve 57 : 561–568, 2018     

Regulation of a Ca2+-activated K+ channel by calcium-sensing receptor involves p38 MAP kinase

By using pharmacological and molecular approaches, we previously showed that the G-protein-coupled, extracellular calcium (Ca2+(o))-sensing receptor (CaR) regulates a large-conductance (approximately 140 pS), Ca(2+)-activated K+ channel [IK(Ca); CAKC] in U87 astrocytoma cells. Here we show that elevated Ca2+(o) stimulates extracellular-signal-regulated kinase (ERK1/2) and p38 MAP kinase (MAPK). The effect of high Ca2+(o) on p38 MAPK but not ERK1/2 is CaR mediated, insofar as transduction with a dominant-negative CaR (R185Q) using recombinant adeno-associated virus (rAAV) attenuated the activation of p38 MAPK but not of ERK1/2. p38 MAPK activation by the CaR is likely to be protein kinase C (PKC) independent, in that the pan-PKC inhibitor GF109203X failed to abolish the high-Ca2+(o)-induced phosphorylation of p38 MAPK. Consistently with our data on the activation of this kinase, we observed that inhibiting p38 MAPK blocked the activation of the CAKC induced by the specific pharmacological CaR activator NPS R-467. In contrast, inhibiting MEK1 only transiently inhibited the activation of this K+ channel by NPS R-467, despite the continued presence of the antagonist. Similarly to the lack of any effect of the PKC inhibitor on the activation of ERK1/2 and p38 MAPK, inhibiting PKC had no effect on NPS R-467-induced activation of this channel. Therefore, our data show that the CaR, acting via p38 MAPK, regulates a large-conductance CAKC in U87 cells, a process that is PKC independent. Large-conductance CAKCs play an important role in the regulation of cellular volume, so our results have important implications for glioma cell volume regulation.     

Endogenous purines modulate K+‐evoked ACh secretion at the mouse neuromuscular junction

At the mouse neuromuscular junction, adenosine triphosphate (ATP) is co‐released with the neurotransmitter acetylcholine (ACh), and once in the synaptic cleft, it is hydrolyzed to adenosine. Both ATP/adenosine diphosphate (ADP) and adenosine modulate ACh secretion by activating presynaptic P2Y₁₃ and A₁, A_2A, and A₃ receptors, respectively. To elucidate the action of endogenous purines on K⁺‐dependent ACh release, we studied the effect of purinergic receptor antagonists on miniature end‐plate potential (MEPP) frequency in phrenic diaphragm preparations. At 10 mM K⁺, the P2Y₁₃ antagonist N‐[2‐(methylthio)ethyl]‐2‐[3,3,3‐trifluoropropyl]thio‐5′‐adenylic acid, monoanhydride with (dichloromethylene)bis[phosphonic acid], tetrasodium salt (AR‐C69931MX) increased asynchronous ACh secretion while the A₁, A₃, and A_2A antagonists 8‐cyclopentyl‐1,3‐dipropylxanthine (DPCPX), (3‐Ethyl‐5‐benzyl‐2‐methyl‐4‐phenylethynyl‐6‐phenyl‐1, 4‐(±)‐dihydropyridine‐3,5‐, dicarboxylate (MRS‐1191), and 2‐(2‐Furanyl)‐7‐(2‐phenylethyl)‐7H‐pyrazolo[4,3‐e][1,2,4]triazolo[1,5‐c]pyrimidin‐5‐amine (SCH‐58261) did not modify neurosecretion. The inhibition of equilibrative adenosine transporters by S‐(p‐nitrobenzyl)‐6‐thioinosine provoked a reduction of 10 mM K⁺‐evoked ACh release, suggesting that the adenosine generated from ATP is being removed from the synaptic space by the transporters. At 15 and 20 mM K⁺, endogenous ATP/ADP and adenosine bind to inhibitory P2Y₁₃ and A₁ and A₃ receptors since AR‐C69931MX, DPCPX, and MRS‐1191 increased MEPP frequency. Similar results were obtained when the generation of adenosine was prevented by using the ecto‐5′‐nucleotidase inhibitor α,β‐methyleneadenosine 5′‐diphosphate sodium salt. SCH‐58261 only reduced neurosecretion at 20 mM K⁺, suggesting that more adenosine is needed to activate excitatory A_2A receptors. At high K⁺ concentration, the equilibrative transporters appear to be saturated allowing the accumulation of adenosine in the synaptic cleft. In conclusion, when motor nerve terminals are depolarized by increasing K⁺ concentrations, the ATP/ADP and adenosine endogenously generated are able to modulate ACh secretion by sequential activation of different purinergic receptors.     

4-aminopyridine causes apoptosis and blocks an outward rectifier K+ channel in malignant astrocytoma cell lines

Among the ion channels and pumps activated by growth factor stimulation, K⁺ channels have been implicated in the growth and proliferation of several cancer cell lines. The role of these channels in central nervous system tumors, however, has not been described. This study used the malignant astrocytoma cell lines U87 and A172. 4-Aminopyridine (4-AP) inhibition of proliferation was dose dependent, and assessment using a TUNEL in situ assay revealed that apoptosis occurred in U87 cells with wild-type p53 but not in A172 cells with mutant p53 (24-hr incubation with 4 mM 4-AP). In patch clamp experiments, we identified two types of K⁺ currents in both cell lines, a charybdotoxin-sensitive Ca²⁺-activated K⁺ channel and a 4-AP-sensitive outward rectifier K⁺ current. The outward rectifier current was blocked by 4-AP in a dose-dependent manner, with half-maximal block occurring at 3.9 mM. The blocking effect of 4 mM 4-AP was noticeable at potentials as low as −65 mV and was statistically significant at −60 mV and above, suggesting that 4-AP-sensitive current is active at physiological potentials. By contrast, charybdotoxin (1 μM) and tetraethylammonium · Cl (2 mM) blocked the Ca²⁺-activated K⁺ channel in both cell lines but had no appreciable effect on cell growth. Our findings reveal that 4-AP inhibits proliferation and the outward rectifier K⁺ channel in both U87 and A172 cells. More studies are needed, however, to describe the mechanism by which K⁺ channels influence proliferation and induce apoptosis. J. Neurosci. Res. 48:122–127, 1997. © 1997 Wiley-Liss, Inc.     

Characterization and regulation of apamin-binding K+ channels in skeletal muscle

The pattern of development and regulation of the apamin receptor (afterhyperpolarization channel) was studied in cultures of skeletal muscle prepared from 1–2-day-old rat pups. Expression was measured by the specific binding of ¹²⁵I-apamin. Apamin binding was virtually undetectable until the time of fusion (3–4 days in culture) of single myoblasts into myotubes. Mature myotubes (5–7 days in vitro) displayed a B_max of 7.4 fmol/mg protein and a K_d of 376 pmol/L. When studied in mature muscle cells, apamin binding was found to increase twofold in response to tetrodotoxin (TTX) and elevated K₀, which resulted in decreased Na_i. In contrast, treatments causing an increase in Na_i, such as monensin and veratridine, caused a decrease in apamin binding. The increase in apamin binding following TTX treatment was due mainly to synthesis of new channels, as the effect was blocked by cycloheximide. Alterations in cytosolic Ca²⁺ by calcium ionophore or Ca-channel blockers were without effect on apamin-sensitive channel expression. We conclude that afterhyperpolarization channel expression is regulated by the level of intracellular Na⁺ ions. © 1996 John Wiley & Sons, Inc.     

A proinvasive role for the Ca2+‐activated K+ channel KCa3.1 in malignant glioma

Glioblastoma multiforme are highly motile primary brain tumors. Diffuse tissue invasion hampers surgical resection leading to poor patient prognosis. Recent studies suggest that intracellular Ca²⁺ acts as a master regulator for cell motility and engages a number of downstream signals including Ca²⁺‐activated ion channels. Querying the REepository of Molecular BRAin Neoplasia DaTa (REMBRANDT), an annotated patient gene database maintained by the National Cancer Institute, we identified the intermediate conductance Ca²⁺‐activated K⁺ channels, KCa3.1, being overexpressed in 32% of glioma patients where protein expression significantly correlated with poor patient survival. To mechanistically link KCa3.1 expression to glioma invasion, we selected patient gliomas that, when propagated as xenolines in vivo, present with either high or low KCa3.1 expression. In addition, we generated U251 glioma cells that stably express an inducible knockdown shRNA to experimentally eliminate KCa3.1 expression. Subjecting these cells to a combination of in vitro and in situ invasion assays, we demonstrate that KCa3.1 expression significantly enhances glioma invasion and that either specific pharmacological inhibition with TRAM‐34 or elimination of the channel impairs invasion. Importantly, after intracranial implantation into SCID mice, ablation of KCa3.1 with inducible shRNA resulted in a significant reduction in tumor invasion into surrounding brain in vivo. These results show that KCa3.1 confers an invasive phenotype that significantly worsens a patient's outlook, and suggests that KCa3.1 represents a viable therapeutic target to reduce glioma invasion. GLIA 2014;62:971–981     

Regulatory volume increase in astrocytes exposed to hypertonic medium requires β1‐adrenergic Na+/K+‐ATPase stimulation and glycogenolysis

The cotransporter of Na⁺, K⁺, 2Cl^–, and water, NKKC1, is activated under two conditions in the brain, exposure to highly elevated extracellular K⁺ concentrations, causing astrocytic swelling, and regulatory volume increase in cells shrunk in response to exposure to hypertonic medium. NKCC1‐mediated transport occurs as secondary active transport driven by Na⁺/K⁺‐ATPase activity, which establishes a favorable ratio for NKCC1 operation between extracellular and intracellular products of the concentrations of Na⁺, K⁺, and Cl^– × Cl^–. In the adult brain, astrocytes are the main target for NKCC1 stimulation, and their Na⁺/K⁺‐ATPase activity is stimulated by elevated K⁺ or the β‐adrenergic agonist isoproterenol. Extracellular K⁺ concentration is normal during regulatory volume increase, so this study investigated whether the volume increase occurred faster in the presence of isoproterenol. Measurement of cell volume via live cell microscopic imaging fluorescence to record fluorescence intensity of calcein showed that this was the case at isoproterenol concentrations of ≥1 µM in well‐differentiated mouse astrocyte cultures incubated in isotonic medium with 100 mM sucrose added. This stimulation was abolished by the β₁‐adrenergic antagonist betaxolol, but not by ICI118551, a β₂‐adrenergic antagonist. A large part of the β₁‐adrenergic signaling pathway in astrocytes is known. Inhibitors of this pathway as well as the glycogenolysis inhibitor 1,4‐dideoxy‐1,4‐imino‐D‐arabinitol hydrochloride and the NKCC1 inhibitors bumetanide and furosemide abolished stimulation by isoproterenol, and it was weakened by the Na⁺/K⁺‐ATPase inhibitor ouabain. These observations are of physiological relevance because extracellular hypertonicity occurs during intense neuronal activity. This might trigger a regulatory volume increase, associated with the post‐excitatory undershoot. © 2014 Wiley Periodicals, Inc.     

New mutation of the Na channel in the severe form of potassium‐aggravated myotonia

Myotonia manifests in several hereditary diseases, including hyperkalemic periodic paralysis (HyperPP), paramyotonia congenita (PMC), and potassium‐aggravated myotonia (PAM). These are allelic disorders originating from missense mutations in the gene that codes the skeletal muscle sodium channel, Nav1.4. Moreover, a severe form of PAM has been designated as myotonia permanens. A new mutation of Nav1.4, Q1633E, was identified in a Japanese family presenting with the PAM phenotype. The proband suffered from cyanotic attacks during infancy. The mutated amino acid residue is located on the EF‐hand calcium‐binding motif in the intracellular C‐terminus. A functional analysis of the mutant channel using the voltage‐clamp method revealed disruption of fast inactivation, a slower rate of current decay, and a depolarized shift in the voltage dependence of availability. This study has identified a new mutation of PAM with a severe phenotype and emphasizes the importance of the C‐terminus for fast inactivation of the sodium channel. Muscle Nerve 39: 666–673, 2009     

Nongenomic actions of progesterone and 17β‐estradiol on the chloride conductance of skeletal muscle

Introduction: Myotonia congenita, caused by mutations in ClC‐1, tends to be more severe in men and is often exacerbated by pregnancy. Methods: We performed whole‐cell patch clamp of mouse muscle chloride currents in the absence/presence of 100 μM progesterone or 17β‐estradiol. Results: 100 μM progesterone rapidly and reversibly shifted the ClC‐1 activation curve of mouse skeletal muscle (V50 changed from ?52.6 ± 9.3 to +35.5 ± 6.7; P < 0.01) and markedly reduced chloride currents at depolarized potentials. 17β‐estradiol at the same concentration had a similar but smaller effect (V50 change from ?57.2 ± 7.6 to ?40.5 ± 9.8; P < 0.05). 1 μM progesterone produced no significant effect. Conclusions: Although the data support the existence of a nongenomic mechanism in mammalian skeletal muscle through which sex hormones at high concentration can rapidly modulate ClC‐1, the influence of hormones on muscle excitability in vivo remains an open question. Muscle Nerve 48 : 589–591, 2013     

Quantification of the functional expression of the Ca2+‐activated K+ channel KCa3.1 on microglia from adult human neocortical tissue

The K_Ca3.1 channel (KCNN4) is an important modulator of microglia responses in rodents, but no information exists on functional expression on microglia from human adults. We isolated and cultured microglia (max 1% astrocytes, no neurons or oligodendrocytes) from neocortex surgically removed from epilepsy patients and employed electrophysiological whole‐cell measurements and selective pharmacological tools to elucidate functional expression of K_Ca3.1. The channel expression was demonstrated as a significant increase in the voltage‐independent current by NS309, a K_Ca3.1/K_Ca2 activator, followed by full inhibition upon co‐application with NS6180, a highly selective K_Ca3.1 inhibitor. A major fraction (79%) of unstimulated human microglia expressed K_Ca3.1, and the difference in current between full activation and inhibition (ΔK_Ca3.1) was estimated at 292 ± 48 pA at −40 mV (n = 75), which equals at least 585 channels per cell. Serial K_Ca3.1 activation/inhibition significantly hyperpolarized/depolarized the membrane potential. The isolated human microglia were potently activated by lipopolysaccharide (LPS) shown as a prominent increase in TNF‐α production. However, incubation with LPS neither changed the K_Ca3.1 current nor the fraction of K_Ca3.1 expressing cells. In contrast, the anti‐inflammatory cytokine IL‐4 slightly increased the K_Ca3.1 current per cell, but as the membrane area also increased, there was no significant change in channel density. A large fraction of the microglia also expressed a voltage‐dependent current sensitive to the K_Ca1.1 modulators NS1619 and Paxilline and an inward‐rectifying current with the characteristics of a K_ir channel. The high functional expression of K_Ca3.1 in microglia from epilepsy patients accentuates the need for further investigations of its role in neuropathological processes. GLIA 2016;64:2065–2078     

Developmental regulation of G protein-gated inwardly-rectifying K+ (GIRK/Kir3) channel subunits in the brain

G protein-gated inwardly-rectifying K(+) (GIRK/family 3 of inwardly-rectifying K(+) ) channels are coupled to neurotransmitter action and can play important roles in modulating neuronal excitability. We investigated the temporal and spatial expression of GIRK1, GIRK2 and GIRK3 subunits in the developing and adult brain of mice and rats using biochemical, immunohistochemical and immunoelectron microscopic techniques. At all ages analysed, the overall distribution patterns of GIRK1-3 were very similar, with high expression levels in the neocortex, cerebellum, hippocampus and thalamus. Focusing on the hippocampus, histoblotting and immunohistochemistry showed that GIRK1-3 protein levels increased with age, and this was accompanied by a shift in the subcellular localization of the subunits. Early in development (postnatal day 5), GIRK subunits were predominantly localized to the endoplasmic reticulum in the pyramidal cells, but by postnatal day 60 they were mostly found along the plasma membrane. During development, GIRK1 and GIRK2 were found primarily at postsynaptic sites, whereas GIRK3 was predominantly detected at presynaptic sites. In addition, GIRK1 and GIRK2 expression on the spine plasma membrane showed identical proximal-to-distal gradients that differed from GIRK3 distribution. Furthermore, although GIRK1 was never found within the postsynaptic density (PSD), the level of GIRK2 in the PSD progressively increased and GIRK3 did not change in the PSD during development. Together, these findings shed new light on the developmental regulation and subcellular diversity of neuronal GIRK channels, and support the contention that distinct subpopulations of GIRK channels exert separable influences on neuronal excitability. The ability to selectively target specific subpopulations of GIRK channels may prove effective in the treatment of disorders of excitability.     

Differential contributions of Ca2+‐activated K+ channels and Na+/K+‐ATPases to the generation of the slow afterhyperpolarization in CA1 pyramidal cells

In many types of CNS neurons, repetitive spiking produces a slow afterhyperpolarization (sAHP), providing sustained, intrinsically generated negative feedback to neuronal excitation. Changes in the sAHP have been implicated in learning behaviors, in cognitive decline in aging, and in epileptogenesis. Despite its importance in brain function, the mechanisms generating the sAHP are still controversial. Here we have addressed the roles of M‐type K⁺ current (I_M), Ca²⁺‐gated K⁺ currents (I_Ca(K)'s) and Na⁺/K⁺‐ATPases (NKAs) current to sAHP generation in adult rat CA1 pyramidal cells maintained at near‐physiological temperature (35 °C). No evidence for I_M contribution to the sAHP was found in these neurons. Both I_Ca(K)'s and NKA current contributed to sAHP generation, the latter being the predominant generator of the sAHP, particularly when evoked with short trains of spikes. Of the different NKA isoenzymes, α₁‐NKA played the key role, endowing the sAHP a steep voltage‐dependence. Thus normal and pathological changes in α₁‐NKA expression or function may affect cognitive processes by modulating the inhibitory efficacy of the sAHP.