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PubMed1996

Differential distribution of classical inwardly rectifying potassium channel mRNAs in the brain: comparison of IRK2 with IRK1 and IRK3.

Distribution of IRK2 inwardly rectifying potassium channel mRNA in the mouse brain was studied using in situ hybridization histochemistry and compared with those of other classical inwardly rectifying potassium channel (IRK1 and IRK3) mRNAs. All these IRK channel mRNAs were detected in neurons, but not in glial cells. Their distribution patterns in the brain were, however, quite divergent: IRK2 mRNA was detected extremely high in granule cells of cerebellum, relatively high in motor trigeminal nucleus and moderate in olfactory bulb, piriform cortex, cerebral cortex, CA1 through CA3 regions of hippocampus, dentate gyrus and pontine nucleus. On the other hand, IRK1 mRNA was expressed throughout whole brain but in particular subsets of neurons, and IRK3 mRNA was in forebrain. Expression of these three IRK mRNAs overlapped in hippocampus, olfactory bulb, and cerebral cortex. This differential distribution of IRK mRNAs suggests that each of these channels has its specific function in regulation of the excitability of brain neurons.

Animals↗
PubMed2006

Differential lidocaine sensitivity of human voltage-gated potassium channels relevant to the auditory system.

HYPOTHESIS: Lidocaine may lead to an alteration in the processing of hearing as observed during tinnitus by inhibiting voltage-gated potassium channels at clinically relevant concentrations. BACKGROUND: Recent molecular evidence suggests that the voltage-gated potassium channels Kv 3.1 and Kv 1.1 play an important functional role in the auditory system. Lidocaine is known to influence the auditory system and may thus exert pharmacological effects on these human potassium channels. METHODS: Patch-clamp recordings were performed on the pharmacologic action of lidocaine on Kv 3.1 channels natively expressed in SH-SY5Y cells and Kv 1.1 channels expressed in HEK 293 cells. RESULTS: Lidocaine reversibly inhibited Kv 3.1 and Kv 1.1 channels in a concentration-dependent manner. The half-maximal inhibitory concentration for conductance block was 607 micromol/L for Kv 3.1 (n=47) and 4,550 micromol/L for Kv 1.1 channels (n=56), respectively. The Hill coefficients were 0.9 and 0.8. Conductance block was voltage dependent for Kv 3.1 but not for Kv 1.1 channels. The midpoint of current activation of both channels was shifted to hyperpolarized potentials. At free plasma concentrations determined during suppression (0.5-1 mg/L; 1.75-3.5 micromol/L) or induction (>1-2 mg/L; >3.5-7 micromol/L) of tinnitus Kv 3.1 and K v1.1 channels would be suppressed by at most 1.5 to 2%. CONCLUSION: Human Kv 3.1 and Kv 1.1 channels exhibited different sensitivities to the inhibitory action of lidocaine. The small effect at clinically relevant concentrations suggests that the physiologic roles of Kv 3.1 and Kv 1.1 channels in auditory neurons seem not to be impaired during the therapeutic or diagnostic application of lidocaine in the auditory system.

Anesthetics, Local↗
PubMed1999

Modulation of HERG potassium channels by extracellular magnesium and quinidine.

Torsades de pointes is a polymorphic ventricular arrhythmia resulting from congenital or drug-induced (acquired) QT prolongation. Pharmacologic suppression of repolarizing potassium currents is one mechanism causing the acquired long QT (LQT) syndrome. Recent studies have linked mutations in a gene encoding a potassium channel subunit (HERG) to the LQT syndrome. Clinical experience indicates that intravenous magnesium sulfate is effective in reversing torsades de pointes, but the molecular basis of this effect is not understood. This study was designed to investigate the effects of extracellular magnesium (Mg2+) on HERG potassium currents. HERG potassium channels were expressed in Xenopus oocytes and in a human cell line and were examined by voltage-clamp methods. Extracellular Mg2+ (0.3-10 mM) caused a concentration-dependent shift in the membrane-potential dependence of HERG channel opening, causing a reduction in K+ current. This effect was much greater than that observed in another human delayed rectifier K+ channel, hKv1.5, suggesting a specific interaction with the HERG channel. Quinidine is an antiarrhythmic drug that also causes torsades de pointes under certain conditions. Quinidine (3 microM) inhibited HERG currents expressed in oocytes by 32.1 +/- 3.2% (n = 5), whereas 1 microM quinidine inhibited HERG currents in tsA201 cells by 75.8 +/- 2.4% (n = 12). Increasing extracellular Mg2+ did not relieve the inhibition by quinidine, but caused additional suppression. These results indicate that extracellular Mg2+ exerts a direct action on HERG potassium channels, resulting in suppression of outward repolarizing potassium current. It is concluded that modulation of this important K+ current is not the mechanism by which intravenous magnesium terminates drug-induced LQT and torsades de pointes. Potent suppression of HERG channel current by quinidine, compared with that of I(Ks) and I(Na), is a likely contributor to torsades de pointes arrhythmias.

Animals↗
PubMed2004

An alternatively spliced isoform of PSD-93/chapsyn 110 binds to the inwardly rectifying potassium channel, Kir2.1.

Inwardly rectifying potassium (Kir) channels are prime determinants of resting membrane potential in neurons. Their subcellular distribution and surface density thus help shape neuronal excitability, yet mechanisms governing the membrane targeting and localization of Kir channels are poorly understood. Here we report a direct interaction between the strong inward rectifier, Kir2.1, and a recently identified splice variant of postsynaptic density-93 (PSD-93), a protein involved the subcellular targeting of ion channels and glutamate receptors at excitatory synapses. Yeast two-hybrid screening of a human brain cDNA library using the carboxyl terminus of Kir2.1 as bait yielded cDNA encoding the first two PDZ domains of PSD-93, but with an extended N-terminal region that diverged from other PSD-93 isoforms. This clone represented the human homologue of the mouse PSD-93 splice variant, PSD-93delta. Reverse transcription-polymerase chain reaction analysis showed diffuse low level PSD-93delta expression throughout the brain, with significantly higher levels in spinal cord. In vitro binding studies revealed that a type I PDZ recognition motif at the extreme C terminus of the Kir2.1 mediates interaction with all three PDZ domains of PSD-93delta, and association between Kir2 channels and PSD-93delta was confirmed further by the ability of anti-Kir2.1 antibodies to coimmunoprecipitate PSD-93delta from rat spinal cord lysates. Functionally, coexpression of Kir2.1 and PSD-93delta had no discernible effect upon channel kinetics but resulted in cell surface Kir2.1 clustering and suppression of channel internalization. We conclude that PSD-93delta is potentially an important regulator of the spatial and temporal distribution of Kir2 channels within neuronal membranes of the central nervous system.

Alternative Splicing↗
PubMed2001

Analysis of a putative voltage-gated prokaryotic potassium channel.

Most of the completely sequenced prokaryotic genomes contain genes of potassium channel homologues, but there is still not much known about the role of these proteins in prokaryotes. Here we describe the large-scale overproduction and purification of a prokaryotic voltage-gated potassium channel homologue, Kch, from Escherichia coli. After successful overproduction of the protein, a specific increase in the potassium permeability of the cells was found. Kch could be purified in large amounts using classical purification methods to prevent aggregation of the protein. The physiological state of the protein was revealed to be a homotetramer and the protein was shown to be localized to the cytoplasmic membrane of the cells. In the course of the localization studies, we found a specific increase in the density of the cytoplasmic membrane on Kch production. This was linked to the observed increase in the protein to lipid ratio in the membranes. Another observed change in the membrane composition was an increase in the cardiolipin to phosphatidylglycerol ratio, which may indicate a specific cardiolipin requirement of Kch. On the basis of some of our results, we discuss a function for Kch in the maintenance of the membrane potential in E. coli.

Cell Membrane↗
PubMed2003

Selective knockout of mouse ERG1 B potassium channel eliminates I(Kr) in adult ventricular myocytes and elicits episodes of abrupt sinus bradycardia.

The ERG1 gene encodes a family of potassium channels. Mutations in human ERG1 lead to defects in cardiac repolarization, referred to as the long QT syndrome. Through homologous recombination in mouse embryonic stem cells the ERG1 B potassium channel transcript was eliminated while the ERG1 A transcript was maintained. Heterologous expression of ERG1 isoforms had previously indicated that the deactivation time course of ERG1 B is 10-fold more rapid than that of ERG1 A. In day-18 fetal +/+ myocytes, I(Kr) exhibited two time constants of deactivation (3,933 +/- 404 and 350 +/- 19 ms at -50 mV), whereas in age-matched ERG1 B(-/-) mice the rapid component was absent. Biexponential deactivation rates (2,039 +/- 268 and 163 +/- 43 ms at -50 mV) were also observed in adult +/+ myocytes. In adult ERG1 B(-/-) myocytes no I(Kr) was detected. Electrocardiogram intervals were similar in +/+ and -/- mice. However, adult -/- mice manifested abrupt spontaneous episodes of sinus bradycardia (>100 ms of slowing) in 6 out of 21 mice. This phenomenon was never observed in +/+ mice (0 out of 16). We conclude that ERG1 B is necessary for I(Kr) expression in the surface membrane of adult myocytes. Knockout of ERG1 B predisposes mice to episodic sinus bradycardia.

Age Factors↗
PubMed2004

A multiprotein trafficking complex composed of SAP97, CASK, Veli, and Mint1 is associated with inward rectifier Kir2 potassium channels.

Strong inward rectifier potassium (Kir2) channels are important in the control of cell excitability, and their functions are modulated by interactions with intracellular proteins. Here we identified a complex of scaffolding/trafficking proteins in brain that associate with Kir2.1, Kir2.2, and Kir2.3 channels. By using a combination of affinity interaction pulldown assays and co-immunoprecipitations from brain and transfected cells, we demonstrated that a complex composed of SAP97, CASK, Veli, and Mint1 associates with Kir2 channels via the C-terminal PDZ-binding motif. We further demonstrated by using in vitro protein interaction assays that SAP97, Veli-1, or Veli-3 binds directly to the Kir2.2 C terminus and recruits CASK. Co-immunoprecipitations indicated that specific Veli isoforms participate in forming distinct protein complexes in brain, where Veli-1 stably associates with CASK and SAP97, Veli-2 associates with CASK and Mint1, and Veli-3 associates with CASK, SAP97, and Mint1. Additionally, immunocytochemistry of rat cerebellum revealed overlapping expression of Kir2.2, SAP97, CASK, Mint1, with Veli-1 in the granule cell layer and Veli-3 in the molecular layer. We propose a model whereby Kir2.2 associates with distinct SAP97-CASK-Veli-Mint1 complexes. In one complex, SAP97 interacts directly with the Kir2 channels and recruits CASK, Veli, and Mint1. Alternatively, Veli-1 or Veli-3 interacts directly with the Kir2 channels and recruits CASK and SAP97; association of Mint1 with the complex requires Veli-3. Expression of Kir2.2 in polarized epithelial cells resulted in targeting of the channels to the basolateral membrane and co-localization with SAP97 and CASK, whereas a dominant interfering form of CASK caused the channels to mislocalize. Therefore, CASK appears to be a central protein of a macromolecular complex that participates in trafficking and plasma membrane localization of Kir2 channels.

Adaptor Proteins, Signal Transducing↗
PubMed2006

Psychiatric presentation of voltage-gated potassium channel antibody-associated encephalopathy. Case report.

Voltage-gated potassium channel antibody encephalopathy, a rare cause of limbic encephalopathy, typically presents with memory impairment and seizures. Psychiatric symptoms have not been emphasised in the literature. Here we describe a 58-year-old man who presented with panic attacks and psychogenic non-epileptic seizures and, later on, developed delusions and hallucinations and then confusion. He was found to have antibodies to voltage-gated potassium channels. Treatment with immuno-modulatory therapy resulted in almost complete recovery.

Antibodies↗
PubMed2005

Involvement of the mitochondrial ATP-sensitive potassium channel in the neuroprotective effect of hyperbaric oxygenation after cerebral ischemia.

In the present study, we investigated whether activation of mitochondrial ATP-sensitive potassium channel is involved in the neuroprotective effect offered by early hyperbaric oxygenation after cerebral ischemia. The selective mitochondrial ATP-sensitive potassium channel antagonist 5-hydroxydecanoate was infused intracerebroventricularly before hyperbaric oxygenation treatment initiated 3 h after middle cerebral artery occlusion for 90 min. Neurological status was evaluated and brains were removed for the measurement of infarct size and immunohistochemical evaluation of apoptosis 24 h after middle cerebral artery occlusion. Early hyperbaric oxygenation treatment improved neurologic deficits and reduced infarct volume, while these effects were reversed by the administration of 5-hydroxydecanoate. Furthermore, early hyperbaric oxygenation significantly decreased the number of apoptotic cells in the peri-infarct cortex 24 h after ischemic insult and this effect was also blocked by 5-hydroxydecanoate. The present findings suggest that early hyperbaric oxygenation therapy prevents apoptosis and promotes neurologic functional recovery after focal cerebral ischemia, and the opening of mitochondrial ATP-sensitive potassium channel plays a role in this antiapoptotic effect of early hyperbaric oxygenation.

Adenosine Triphosphate↗
PubMed2003

Tityustoxin-K(alpha) blockade of the voltage-gated potassium channel Kv1.3.

1. We investigated the action of TsTX-Kalpha on cloned Kv1.3 channels of the Shaker subfamily of voltage-gated potassium channels, using the voltage-clamp technique. Highly purified TsTX-Kalpha was obtained from the venom of the Brazilian scorpion Tityus serrulatus using a new purification protocol. Our results show that TsTX-Kalpha blocks Kv1.3 with high affinity in two expression systems. 2. TsTX-Kalpha blockade of Kv1.3 channels expressed in Xenopus oocytes was found to be completely reversible and to exhibit a pH dependence. The K(D) was 3.9 nM at pH 7.5, 9.5 nM at pH 7.0 and 94.5 nM at pH 6.5. 3. The blocking properties of TsTX-Kalpha in a mammalian cell line (L929), stably transfected to express Kv1.3, were studied using the patch-clamp technique. In this preparation, the toxin had a K(D) of 19.8 nM at pH 7.4. 4. TsTX-Kalpha was found to affect neither the voltage-dependence of activation, nor the activation and deactivation time constants. The block appeared to be independent of the transmembrane voltage and the toxin did not interfere with the C-type inactivation process. 5. Taken as a whole, our findings indicate that TsTX-Kalpha acts as a simple blocker of Kv1.3 channels. It is concluded that this toxin is a useful tool for probing not only the physiological roles of Kv1.2, but also those mediated by Kv1.3 channels.

Animals↗
PubMed2004

Selective intermediate-/small-conductance calcium-activated potassium channel (KCNN4) blockers are potent and effective therapeutics in experimental brain oedema and traumatic brain injury caused by acute subdural haematoma.

Early deterioration and death after brain injury is often the result of oedema in the injured and peri-lesional tissue. So far, no pharmacotherapy is available that exhibits significant brain oedema-reducing efficacy in patients. We selected two low molecular weight compounds from different chemical classes, a triazole (1-[(2-chlorophenyl)diphenylmethyl]-1,2,3-triazole) and a cyclohexadiene (methyl 4-[4-chloro-3-(trifluoromethyl)phenyl]-6-methyl-3-oxo-1,4,7-tetrahydroisobenzofuran-5-carboxylate) to characterize their pharmacological properties on KCNN4 channels (intermediate/small conductance calcium-activated potassium channel, subfamily N, member 4) in vitro as well as in vivo. In vitro we replaced potassium by rubidium (Rb+) and determined Rb+ fluxes evoked by 10 micro m of the calcium ionophore A23187 on C6BU1 rat glioma cells. Compared with known KCNN4 blockers, such as clotrimazole (IC50=360 +/- 12 nm) and charybdotoxin (IC50=3.3 +/- 1.9 nm), the triazole and cyclohexadiene were considerably more potent than clotrimazole and displayed similar potencies (IC50=12.1 +/- 8.8 and 13.3 +/- 4.7 nm, respectively). In the rat acute subdural haematoma model, both the triazole and cyclohexadiene displayed reduction of brain water content (-26% at 0.3 mg/kg and -24% at 0.01 mg/kg) and reduction of the intracranial pressure (-46% at 0.1 mg/kg and -60% at 0.003 mg/kg) after 24 h when administered as a 4-h infusion immediately after brain injury. When infarct volumes were determined after 7 days, the triazole as well as the cyclohexadiene displayed strong neuroprotective efficacy (-52% infarct volume reduction at 1.2 mg/kg and -43% at 0.04 mg/kg, respectively). It is concluded that blockade of KCNN4 channels is a new pharmacological approach to attenuate acute brain damage caused by traumatic brain injury.

Animals↗
PubMed2003

Interaction of agitoxin2, charybdotoxin, and iberiotoxin with potassium channels: selectivity between voltage-gated and Maxi-K channels.

To gain insight into the molecular determinants that define the specificity of interaction of pore-blocking peptides, such as agitoxin 2 (AgTX2), charybdotoxin (ChTX), and iberiotoxin (IbTX) with the Shaker-type voltage-gated potassium channel Kv1.3, or the large-conductance Ca(2+)-activated K(+) (Maxi-K) channel, homology models of these channels were generated based on the crystal structure of the bacterial, KcsA, potassium channel. Peptide-channel complexes were analyzed to evaluate the predicted interaction interfaces between the peptides and the channels' outer vestibules. The docking model, for either AgTX2 or ChTX with the Kv1.3 channel, predicts a novel hydrogen bonding interaction between the Asn30 side-chain of the peptide and the Asp381 side-chain of the channel. This interaction is consistent with the >500-fold decreased potency of both AgTX2 and ChTX mutants at position 30 for the Shaker channel [(Ranganathan et al., Neuron 1996;16:131-139); (Goldstein et al., Neuron 1994;12:1377-1388)]. This hydrogen bonding interaction also suggests that Gly30 in IbTX may be the critical determinant for its lack of activity against Shaker Kv channels. The model of the Maxi-K channel reveals a narrower and more structurally restrained outer vestibule in which the aromatic residues Phe266 and Tyr294 may stabilize binding of IbTX and ChTX by pi-pi stacking with the aromatic residues Trp14 and Tyr36 of the peptides. This study also suggests that the extra net negative charge of IbTX is not related to the selectivity of this peptide for the Maxi-K channel.

Amino Acid Sequence↗
PubMed2000

Kir2.1 Potassium channels and corneal epithelia.

PURPOSE: To determine the existence of inward rectifier (Kir2.1) sequences in mRNA from corneal epithelium and endothelium. METHODS: cDNA library construction, cloning, PCR, patch clamp. RESULTS. Both the corneal epithelium and endothelium contain mRNA for Kir2.1 inwardly rectifying potassium channels. When the cDNA is transfected into Chinese hamster ovary cells, the channel currents match those expected from Kir2.1 inward rectifiers. CONCLUSIONS: The mRNA for Kir2.1 potassium channels exists in corneal epithelium and endothelium. Therefore, Kir2.1 inwardly rectifying potassium channels probably make some contributions to the resting voltages of cornea epithelium and endothelium. Previous data, however, suggest that they are probably not the dominant contributors in these preparations.

Amino Acid Sequence↗
PubMed2004

Identification and distribution of a two-pore domain potassium channel in the CNS of Aplysia californica.

A cDNA encoding a potassium channel of the two-pore domain family (K2p) of leak channels was cloned from the CNS of the marine opisthobranch Aplysia californica. This is the first sequence of the K2p family identified in molluscs and has been named AcK2p1. The deduced amino acid sequence is homologous to channels of the mammalian two-pore domain halothane inhibited (THIK) subfamily, bearing 46% identity to THIK-1 (KCNK 13) and 48% to THIK-2 (KCNK12). We used in-situ hybridization to analyze the distribution of this class of channels in the CNS. AcK2p1 is specifically expressed in many central neurons of all major ganglia including the largest identified neurons MCC, R2 and LP1. The highest expression of AcK2p1 was detected in an asymmetrical and distinct cluster of up to 30 cells located at the dorsal-medial region of the right pleural ganglion. The neuron-specific distribution seen in the molluscan CNS is consistent with data from mammals that indicate THIK is only expressed in restricted neuronal populations, suggesting its involvement in both the maintenance of neuronal phenotype and in the specific functional role of these neurons in their respective networks.

Amino Acid Sequence↗
PubMed2003

An interaction domain in Slob necessary for its binding to the slowpoke calcium-dependent potassium channel.

Slob modulates the activity of the Drosophila Slowpoke calcium-dependent potassium channel (dSlo) via its direct binding to the channel. To characterize the molecular detail of the protein-protein interaction between Slob and dSlo, we constructed a series of Slob mutants that are progressively truncated at either the carboxyl or amino terminal end, and examined the binding of these Slob mutants to dSlo using a co-immunoprecipitation approach. Our data suggest that a small region of 42 amino acids (residues 191-233) in Slob is essential for Slob to interact with the dSlo channel.

Animals↗
PubMed2004

Vasorelaxing effects of flavonoids: investigation on the possible involvement of potassium channels.

A flavonoid-rich diet has been associated with a lower incidence of cardiovascular diseases, probably because of the antioxidant and vasoactive properties of flavonoids. Indeed, many flavonoids show vasorelaxing properties, due to different and often not yet completely clarified mechanisms of action. Among them, the activation of vascular potassium channels has been indicated as a possible pathway, accounting, at least in part, for the vasodilatory action of some flavonoid derivatives, such as apigenin and dioclein. Therefore, this work aims at evaluating, on in vitro isolated rat aortic rings, the endothelium-independent vasorelaxing effects of a number of flavonoid derivatives, to identify a possible activation of calcium-activated and/or ATP-sensitive potassium channels and to indicate some possible structure-activity relationships. Among the several flavonoids submitted to the pharmacological assay, only baicalein and quercetagetin were almost completely ineffective, while quercetin, hesperidin, quercitrin and rhoifolin exhibited only a partial vasorelaxing effect. On the contrary, acacetin, apigenin, chrysin, hesperetin, luteolin, pinocembrin, 4'-hydroxyflavanone, 5-hydroxyflavone, 5-methoxyflavone, 6-hydroxyflavanone and 7-hydroxyflavone, belonging to the chemical classes of flavones and flavanones, showed full vasorelaxing effects. The vasodilatory activity of hesperetin, luteolin, 5-hydroxyflavone and 7-hydroxyflavone were antagonised by tetraethylammonium chloride, indicating the possible involvement of calcium-activated potassium channels. Moreover, iberiotoxin clearly antagonised the effects of 5-hydroxyflavone, indicating the probable importance of a structural requirement (the hydroxy group in position 5) for a possible interaction with large-conductance, calcium-activated potassium channels. Finally, glibenclamide inhibited the vasorelaxing action of luteolin and 5-hydroxyflavone, suggesting that ATP-sensitive potassium channels may also be involved in their mechanism of action.

Animals↗
PubMed1999

Corticosteroids alter G protein inwardly rectifying potassium channels protein levels in hippocampal subfields.

Corticosterone or cortisol, stress hormones in rat and human, respectively, alter neurotransmitter receptor-mediated responses in the brain. Corticosterone could alter these responses by modifying any component of the receptor-effector pathway. Many of these receptors are linked to guanine nucleotide regulatory proteins (G proteins) which, in turn, can activate second messenger systems and/or ion channels, such as G protein inwardly rectifying potassium channels (GIRK). The aim of these experiments was to determine whether corticosterone treatment altered the levels of GIRK proteins in rat hippocampus. Corticosterone treatment selectively altered the levels of GIRK1 and GIRK2 (measured on immunoblots) depending on the subfield of the hippocampus examined. These data lend credence to the hypothesis that corticosterone differentially alters neurotransmitter receptor-mediated responses dependent on the brain area.

Adrenalectomy↗
PubMed2005

Regulation of the voltage-gated potassium channel KCNQ4 in the auditory pathway.

The potassium channel KCNQ4, expressed in the mammalian cochlea, has been associated tentatively with an outer hair cell (OHC) potassium current, I(K,n), a current distinguished by an activation curve shifted to exceptionally negative potentials. Using CHO cells as a mammalian expression system, we have examined the properties of KCNQ4 channels under different phosphorylation conditions. The expressed current showed the typical KCNQ4 voltage-dependence, with a voltage for half-maximal activation (V(1/2)) of -25 mV, and was blocked almost completely by 200 microM linopirdine. Application of 8-bromo-cAMP or the catalytic sub-unit of PKA shifted V(1/2) by approximately -10 and -20 mV, respectively. Co-expression of KCNQ4 and prestin, the OHC motor protein, altered the voltage activation by a further -15 mV. Currents recorded with less than 1 nM Ca(2+) in the pipette ran down slowly (12% over 5 min). Buffering the pipette Ca(2+) to 100 nM increased the run-down rate sevenfold. Exogenous PKA in the pipette prevented the effect of elevated [Ca(2+)](i) on run-down. Inhibition of the calcium binding proteins calmodulin or calcineurin by W-7 or cyclosporin A, respectively, also prevented the calcium-dependent rapid run-down. We suggest that KCNQ4 phosphorylation via PKA and coupling to a complex that may include prestin can lead to the negative activation and the negative resting potential found in adult OHCs.

Animals↗