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PubMed2000

Colocalization and coassembly of two human brain M-type potassium channel subunits that are mutated in epilepsy.

Acetylcholine excites many central and autonomic neurons through inhibition of M-channels, slowly activating, noninactivating voltage-gated potassium channels. We here provide information regarding the in vivo distribution and biochemical characteristics of human brain KCNQ2 and KCNQ3, two channel subunits that form M-channels when expressed in vitro, and, when mutated, cause the dominantly inherited epileptic syndrome, benign neonatal familial convulsions. KCNQ2 and KCNQ3 proteins are colocalized in a somatodendritic pattern on pyramidal and polymorphic neurons in the human cortex and hippocampus. Immunoreactivity for KCNQ2, but not KCNQ3, is also prominent in some terminal fields, suggesting a presynaptic role for a distinct subgroup of M-channels in the regulation of action potential propagation and neurotransmitter release. KCNQ2 and KCNQ3 can be coimmunoprecipitated from brain lysates. Further, KCNQ2 and KCNQ3 are coassociated with tubulin and protein kinase A within a Triton X-100-insoluble protein complex. This complex is not associated with low-density membrane rafts or with N-methyl-d-aspartate receptors, PSD-95 scaffolding proteins, or other potassium channels tested. Our studies thus provide a view of a signaling complex that may be important for cognitive function as well as epilepsy. Analysis of this complex may shed light on the unknown transduction pathway linking muscarinic acetylcholine receptor activation to M-channel inhibition.

Brain↗
PubMed2001

Ion channels and epilepsy.

Ion channels provide the basis for the regulation of excitability in the central nervous system and in other excitable tissues such as skeletal and heart muscle. Consequently, mutations in ion channel encoding genes are found in a variety of inherited diseases associated with hyper- or hypoexcitability of the affected tissue, the so-called 'channelopathies.' An increasing number of epileptic syndromes belongs to this group of rare disorders: Autosomal dominant nocturnal frontal lobe epilepsy is caused by mutations in a neuronal nicotinic acetylcholine receptor (affected genes: CHRNA4, CHRNB2), benign familial neonatal convulsions by mutations in potassium channels constituting the M-current (KCNQ2, KCNQ3), generalized epilepsy with febrile seizures plus by mutations in subunits of the voltage-gated sodium channel or the GABA(A) receptor (SCN1B, SCN1A, GABRG2), and episodic ataxia type 1-which is associated with epilepsy in a few patients--by mutations within another voltage-gated potassium channel (KCNA1). These rare disorders provide interesting models to study the etiology and pathophysiology of disturbed excitability in molecular detail. On the basis of genetic and electrophysiologic studies of the channelopathies, novel therapeutic strategies can be developed, as has been shown recently for the antiepileptic drug retigabine activating neuronal KCNQ potassium channels.

Ataxia↗
PubMed1998

A pore mutation in a novel KQT-like potassium channel gene in an idiopathic epilepsy family.

Epileptic disorders affect about 20-40 million people worldwide, and 40% of these are idiopathic generalized epilepsies (IGEs; ref. 1). Most of the IGEs that are inherited are complex, multigenic diseases. To address basic mechanisms for epilepsies, we have focused on one well-defined class of IGEs with an autosomal-dominant mode of inheritance: the benign familial neonatal convulsions (BFNC; refs 2,3). Genetic heterogeneity of BFNC has been observed. Two loci, EBN1 and EBN2, have been mapped by linkage analysis to chromosome 20q13 (refs 5,6) and chromosome 8q24 (refs 7,8), respectively. By positional cloning, we recently identified the gene for EBN1 as KCNQ2 (ref. 9). This gene, a voltage-gated potassium channel, based on homology, is a member of the KQT-like family. Here we describe an additional member, KCNQ3. We mapped this new gene to chromosome 8, between markers D8S256 and D8S284 on a radiation hybrid map. We screened KCNQ3 for mutations in the large BFNC family previously linked to chromosome 8q24 in the same marker interval. We found a missense mutation in the critical pore region in perfect co-segregation with the BFNC phenotype. The same conserved amino acid is also mutated in KVLQT1 (KCNQ1) in an LQT patient. KCNQ2, KCNQ3 and undiscovered genes of the same family of K+ channels are strong candidates for other IGEs.

Amino Acid Sequence↗
PubMed2005

[3H]linopirdine binding to rat brain membranes is not relevant for M-channel interaction.

Linopirdine was developed as a cognitive enhancing molecule and demonstrated to specifically block the potassium current generated by the brain specific KCNQ2-KCNQ3 proteins (M-channel). In this study we investigated the relevance of [(3)H]linopirdine binding in rat brain extracts to the interaction with the M-channel proteins. Our results confirm the presence of a high affinity site for [(3)H]linopirdine in rat brain tissues (KD = 10 nM) but we also identified a high affinity binding site for [(3)H]linopirdine in rat liver tissues (KD = 9 nM). Competition experiments showed that [(3)H]linopirdine is displaced by unlabelled linopirdine with comparable affinities from its binding sites on rat brain and rat liver membranes. [(3)H]linopirdine was completely displaced by a set of cytochrome P450 (CYP450) ligands suggesting that [(3)H]linopirdine binding to rat brain and liver membranes is linked to CYP450 interaction. The testing of CYP450 ligands on the M-channel activity, using a Rb(+) efflux assay on cells expressing the KCNQ2-KCNQ3 proteins, demonstrated that [(3)H]linopirdine binding results cannot be correlated to M-channel inhibition. The results obtained in this study demonstrate that [(3)H]linopirdine binding to rat brain and rat liver membranes is representative for CYP450 interaction and not relevant for the binding to the M-channel proteins.

Animals↗
PubMed2006

Molecular genetics of infantile nervous system channelopathies.

Inherited or de novo mutations in at least a dozen genes encoding ion channels may present as paroxysmal disorders during the neonatal period or first year of life. These channelopathies include genes encoding voltage-gated channels specific for sodium (SCN1A, SCN2A, SCN1B, SCN9A) and potassium (KCNQ2, KCNQ3) which account for a variety of epilepsy phenotypes ranging from mild, such as Benign familial neonatal seizures (BFNS) to severe, such as Dravet syndrome (severe myoclonic epilepsy of infancy, SMEI) and the rare and unusual syndrome paroxysmal extreme pain disorder (PEPD). Ligand-gated channels involved include the GABA(A) receptor in a variety of epilepsy phenotypes and the human glycine receptor. Mutations in five genes encoding subunits of this receptor and accessory molecules underlie hyperekplexia or stiff-baby syndrome. All these conditions are rare but correct diagnosis is of value not only for genetic counselling but to allow the specific treatment which is available.

Channelopathies↗
PubMed2005

Regulation of KCNQ4 potassium channel prepulse dependence and current amplitude by SGK1 in Xenopus oocytes.

The KCNQ gene family comprises voltage-gated potassium channels expressed in epithelial tissues (KCNQ1, KCNQ5), inner ear structures (KCNQ1, KCNQ4) and the brain (KCNQ2-5). KCNQ4 is expressed in inner and outer hair cells of the inner ear where it determines electrical excitability. Accordingly, loss of function mutations of the KCNQ4 gene cause hearing loss. Several K+ channels including the closely related KCNQ1/KCNE1 channel are regulated by the serum- and glucocorticoid-inducible kinase (SGK) family. The present study utilized the Xenopus oocyte system to explore effects of SGK isoforms on KCNQ4 mediated K(+)-currents: KCNQ4 channels activated in a voltage dependent manner with half maximal activation at -10 mV. The peak channel activity was significantly increased by prepulsing. Coexpression of wild type SGK1 but not coexpression of the inactive mutant (K127N)SGK1 significantly increased current amplitudes (by 67 %) and significantly increased the resting potential of KCNQ4 expressing oocytes. Here we describe for the first time a prepulse dependence of KCNQ4 channels with increased currents after hyperpolarizing prepulses. Coexpression of SGK1 significantly attenuated the effect of prepulsing on peak currents. Mutation of Ser to Asp or Ala in the putative phosphorylation consensus sequence in KCNQ4 significantly decreased the sensitivity to SGK1-coexpression. In conclusion, SGK1 regulates current amplitudes and kinetic properties of KCNQ4 channel activity, an effect sensitive to mutations in the SGK1 consensus sequence of the channel.

Animals↗
PubMed2006

Functional coassembly of KCNQ4 with KCNE-beta- subunits in Xenopus oocytes.

The KCNQ gene family comprises voltage-gated potassium channels expressed in epithelial tissues (KCNQ1, KCNQ5), inner ear structures (KCNQ1, KCNQ4) and the brain (KCNQ2-5). KCNQ4 is expressed in inner and outer hair cells of the inner ear where it influences electrical excitability and cell survival. Accordingly, loss of function mutations of the KCNQ4 gene cause hearing loss in humans and functional k.o.-mice show progressive degeneration of outer hair cells (OHCs). However, characteristic electrophysiological features of the native KCNQ4- carried current I(K,n) in OHCs are not recapitulated by expression of KCNQ4 channels in heterologous expression systems. This might suggest modulation of KCNQ4 by interacting KCNE Beta-subunits, which are known to modify the properties of the closely related KCNQ1. The present study explored whether transcripts of the KCNE isoforms could be identified in OHC mRNA and whether the subunits modulate KCNQ4 function. RT-PCR indeed yielded transcripts of all five KCNEs in OHCs. Coexpression of the KCNE- Beta-subunits with human KCNQ4 in the Xenopus laevis oocyte expression system revealed that all KCNEs modulate KCNQ4 voltage dependence, protein stability and ion selectivity of hKCNQ4 in Xenopus oocytes. The deafness-associated Jervell and Lange- Nielsen syndrome (JLNS) mutation KCNE1(D76N) impairs KCNQ4-function whereas the Romano-Ward syndrome (RWS) mutant KCNE1(S74L), which shows normal hearing in patients, does not impair KCNQ4 channel function. In conclusion, KCNEs are presumably coexpressed with KCNQ4 in hair cells from the organ of Corti and might regulate KCNQ4 functional properties, effects that could be important under physiological and pathophysiological conditions.

Animals↗
PubMed2003

RNA microarray analysis of channels and transporters in normal and fetal Down syndrome (trisomy 21) brain.

A couple of transporters and channels has been proposed as candidate genes involved in the pathomechanisms leading to the neurodevelopmental abnormalities and the phenotype of Down Syndrome (DS, trisomy 21). No systematic study, however, has been carried out showing the concomitant expression of several candidate RNAs during fetal life. It was therefore the aim of the study to apply an array of 96 brain RNAs mainly consisting of channels and transporters to show their expressional levels in fetal DS brain at the early second trimester. Brain RNA was extracted from fetal cortex of the 18-19th week of gestation of controls and DS individuals and used for the GEArray Q Series Human Neuroscience-1/Ion Channels & Transporters analysis. 15 out of 96 RNAs of the array were observed on the films in both groups during this gestational period consisting of genes for potassium, sodium, calcium channels and transporters (ASIC3, ATP1B1, CACNA1B, KCNB2, KCNC1, KCND2, KCNF1, KCNN1, KCNN3, hKCa4, KCNQ2, lipid transfer protein II, SCN2B, acetyl choline transporter, glutamate transporter3). There was no statistically significant difference between the control and the DS group. We provide information on the developmental expression of the aforementioned 15 RNAs and the absence of the residual examined 81 RNAs at the 18th/19th week of gestation in fetal cortex that was never reported before and show that channels and transporters present with unchanged expression in fetal DS brain.

Cerebral Cortex↗
PubMed2006

Molecular analyses of KCNQ1-5 potassium channel mRNAs in rat and guinea pig inner ears: expression, cloning, and alternative splicing.

CONCLUSION: Expression of neuronal Kcnq gene family transcripts in the inner ear provides further evidence for cochlear M-type currents and for complex molecular heterogeneities of voltage-gated potassium channels composed of various KCNQ subunits and/or alternative splice variants. Furthermore, important roles in regulation of cellular excitability in the auditory system, and hearing disorders related to (hyper)excitability, e.g. tinnitus, are implied. BACKGROUND: Voltage-gated potassium channels play key roles in hearing, as evidenced by deafness resulting from disruption of genes encoding, for example, KCNQ1 or KCNQ4 subunits. Other members of the Kcnq gene family (Kcnq2, 3, and 5) are the molecular correlates of M currents, which regulate neuronal excitability. The expression of the latter has not previously been thoroughly investigated in the inner ear. OBJECTIVE: The aim of this study was to identify genetic correlates of M currents, previously identified in cochlear hair cells by electrophysiological methods. MATERIALS AND METHODS: Expression of Kcnq genes was investigated by reverse transcription-polymerase chain reaction (RT-PCR) using subtype-specific primers with total RNA isolated from whole guinea pig or rat cochlea as template. PCR products were confirmed by direct DNA sequencing. RESULTS: All members of the Kcnq family were expressed in guinea pig and rat cochlea. Cochlear expression of Kcnq2 exhibited two alternatively spliced forms, lacking exons 8, 15a, and 8, 12a, 15a, respectively. Novel molecular sequence data, e.g. guinea pig Kcnq cDNA sequences, were deposited in GenBank (AY684985-AY684990).

Alternative Splicing↗
PubMed2000

M-type K+ currents in rat cultured thoracolumbar sympathetic neurones and their role in uracil nucleotide-evoked noradrenaline release.

Cultured sympathetic neurones are depolarized and release noradrenaline in response to extracellular ATP, UDP and UTP. We examined the possibility that, in neurones cultured from rat thoracolumbar sympathetic ganglia, inhibition of the M-type potassium current might underlie the effects of UDP and UTP. Reverse transcriptase-polymerase chain reaction indicated that the cultured cells contained mRNA for P2Y(2)-, P2Y(4)- and P2Y(6)-receptors as well as for the KCNQ2- and KCNQ3-subunits which have been suggested to assemble into M-channels. In cultures of neurones taken from newborn as well as from 10 day-old rats, oxotremorine, the M-channel blocker Ba(2+) and UDP all released previously stored [(3)H]-noradrenaline. The neurones possessed M-currents, the kinetic properties of which were similar in neurones from newborn and 9 - 12 day-old rats. UDP, UTP and ATP had no effect on M-currents in neurones prepared from newborn rats. Oxotremorine and Ba(2+) substantially inhibited the current. ATP also had no effect on the M-current in neurones prepared from 9 - 12 day-old rats. Oxotremorine and Ba(2+) again caused marked inhibition. In contrast to cultures from newborn animals, UDP and UTP attenuated the M-current in neurones from 9 - 12 day-old rats; however, the maximal inhibition was less than 30%. The results indicate that inhibition of the M-current is not involved in uracil nucleotide-induced transmitter release from rat cultured sympathetic neurones during early development. M-current inhibition may contribute to release at later stages, but only to a minor extent. The mechanism leading to noradrenaline release by UDP and UTP remains unknown.

Adenosine Triphosphate↗
PubMed2001

KCNQ4 channel activation by BMS-204352 and retigabine.

Activation of potassium channels generally reduces cellular excitability, making potassium channel openers potential drug candidates for the treatment of diseases related to hyperexcitabilty such as epilepsy, neuropathic pain, and neurodegeneration. Two compounds, BMS-204352 and retigabine, presently in clinical trials for the treatment of stroke and epilepsy, respectively, have been proposed to exert their protective action via an activation of potassium channels. Here we show that KCNQ4 channels, stably expressed in HEK293 cells, were activated by retigabine and BMS-204352 in a reversible and concentration-dependent manner in the concentration range 0.1-10 microM. Both compounds shifted the KCNQ4 channel activation curves towards more negative potentials by about 10 mV. Further, the maximal current obtainable at large positive voltages was also increased concentration-dependently by both compounds. Finally, a pronounced slowing of the deactivation kinetics was induced in particular by BMS-204352. The M-current blocker linopirdine inhibited the baseline current, as well as the BMS-204352-induced activation of the KCNQ4 channels. KCNQ2, KCNQ2/Q3, and KCNQ3/Q4 channels were activated to a similar degree as KCNQ4 channels by 10 microM of BMS-204352 and retigabine, respectively. The compounds are, thus, likely to be general activators of M-like currents.

Anticonvulsants↗
PubMed2002

KCNE4 is an inhibitory subunit to the KCNQ1 channel.

KCNE4 is a membrane protein belonging to a family of single transmembrane domain proteins known to have dramatic effect on the gating of certain potassium channels. However, no functional role of KCNE4 has been suggested so far. In the present paper we demonstrate that KCNE4 is an inhibitory subunit to KCNQ1 channels. Co-expression of KCNQ1 and KCNE4 in Xenopus oocytes completely inhibited the KCNQ1 current. This was reproduced in mammalian CHO-K1 cells. Experiments with delayed expression of mRNA coding for KCNE4 in KCNQ1-expressing oocytes suggested that KCNE4 exerts its effect on KCNQ1 channels already expressed in the plasma membrane. This notion was supported by immunocytochemical studies and Western blotting, showing no significant difference in plasma membrane expression of KCNQ1 channels in the presence or absence of KCNE4. The impact of KCNE4 on KCNQ1 was specific since no effect of KCNE4 could be detected if co-expressed with KCNQ2-5 channels or hERG1 channels. RT-PCR studies revealed high KCNE4 expression in embryos and adult uterus, where significant expression of KCNQ1 channels has also been demonstrated.

Animals↗
PubMed2026

Early infantile developmental and epileptic encephalopathy: clinical spectrum, diagnosis, outcomes, and evolving treatment strategies.

Early infantile developmental and epileptic encephalopathy (EIDEE) is among the most severe epilepsy syndromes, with onset before three months of age and an estimated incidence of approximately 10 per 100,000 live births. The 2022 International League Against Epilepsy classification unified the historically distinct Ohtahara syndrome and early myoclonic encephalopathy under a single diagnostic framework defined by frequent drug-resistant tonic and/or myoclonic seizures, an abnormal neurological examination, and an abnormal interictal electroencephalogram-most characteristically a burst-suppression pattern. This narrative review synthesizes the clinical, electrophysiological, neuroimaging, genetic, and therapeutic literature within the EIDEE framework. The clinical phenotype is characterized by central hypotonia, postnatal microcephaly, cortical visual impairment, and age-dependent syndromic evolution toward infantile epileptic spasms syndrome or Lennox-Gastaut syndrome in the majority of patients. Electroencephalography remains essential for syndromic classification, while systematic metabolic screening and early trio whole-exome or whole-genome sequencing are central to the etiologic workup, achieving diagnostic yields of 60-65%. The most commonly identified genetic causes include STXBP1, KCNQ2, and SCN2A variants. Outcomes are poor overall and strongly etiology-dependent: vitamin-responsive disorders carry a substantially more favorable prognosis, whereas mortality reaches 25% in genetic cohorts. Genotype-guided pharmacotherapy is now applicable to a clinically meaningful subset of patients, with sodium channel blockers, potassium channel openers, and emerging antisense oligonucleotide therapies representing important therapeutic advances. Gene therapy trials are underway but have encountered early safety signals, underscoring the vulnerability of this population. Critical unmet needs include earlier molecular diagnosis, precision therapies targeting developmental outcomes beyond seizure control, and prospective international registries to characterize the long-term natural history of EIDEE.

Humans↗
PubMed2005

Molecular determinants of KCNQ (Kv7) K+ channel sensitivity to the anticonvulsant retigabine.

Epilepsy is caused by an electrical hyperexcitability in the CNS. Because K+ channels are critical for establishing and stabilizing the resting potential of neurons, a loss of K+ channels could support neuronal hyperexcitability. Indeed, benign familial neonatal convulsions, an autosomal dominant epilepsy of infancy, is caused by mutations in KCNQ2 or KCNQ3 K+ channel genes. Because these channels contribute to the native muscarinic-sensitive K+ current (M current) that regulates excitability of numerous types of neurons, KCNQ (Kv7) channel activators would be effective in epilepsy treatment. A compound exhibiting anticonvulsant activity in animal seizure models is retigabine. It specifically acts on the neuronally expressed KCNQ2-KCNQ5 (Kv7.2-Kv7.5) channels, whereas KCNQ1 (Kv7.1) is not affected. Using the differential sensitivity of KCNQ3 and KCNQ1 to retigabine, we constructed chimeras to identify minimal segments required for sensitivity to the drug. We identified a single tryptophan residue within the S5 segment of KCNQ3 and also KCNQ2, KCNQ4, and KCNQ5 as crucial for the effect of retigabine. Furthermore, heteromeric KCNQ channels comprising KCNQ2 and KCNQ1 transmembrane domains (attributable to transfer of assembly properties from KCNQ3 to KCNQ1) are retigabine insensitive. Transfer of the tryptophan into the KCNQ1 scaffold resulted in retigabine-sensitive heteromers, suggesting that the tryptophan is necessary in all KCNQ subunits forming a functional tetramer to confer drug sensitivity.

Animals↗
PubMed2005

Differential roles of S6 domain hinges in the gating of KCNQ potassium channels.

Voltage-gated K+ channel activation is proposed to result from simultaneous bending of all S6 segments away from the central axis, enlarging the aperture of the pore sufficiently to permit diffusion of K+ into the water-filled central cavity. The hinge position for the bending motion of each S6 segment is proposed to be a Gly residue and/or a Pro-Val-Pro motif in Kv1-Kv4 channels. The KCNQ1 (Kv7.1) channel has Ala-336 in the Gly-hinge position and Pro-Ala-Gly. Here we show that mutation of Ala-336 to Gly in KCNQ1 increased current amplitude and shifted the voltage dependence of activation to more negative potentials, consistent with facilitation of hinge activity that favors the open state. In contrast, mutation of Ala-336 to Cys or Thr shifted the voltage dependence of activation to more positive potentials and reduced current amplitude. Mutation of the putative Gly hinge to Ala in KCNQ2 (Kv7.2) abolished channel function. Mutation-dependent changes in current amplitude, but not kinetics, were found in heteromeric KCNQ1/KCNE1 channels. Mutation of the Pro or Gly of the Pro-Ala-Gly motif to Ala abolished KCNQ1 function and introduction of Gly in front of the Ala-mutations partially recovered channel function, suggesting that flexibility at the PAG is important for channel activation.

Amino Acid Sequence↗
PubMed2005

Electrophysiological and molecular identification of hepatocellular volume-activated K+ channels.

Although K+ channels are essential for hepatocellular function, it is not known which channels are involved in the regulatory volume decrease (RVD) in these cells. We have used a combination of electrophysiological and molecular approaches to describe the potential candidates for these channels. The dialysis of short-term cultured rat hepatocytes with a hypotonic solution containing high K+ and low Cl- concentration caused the slow activation of an outward, time-independent current under whole-cell configuration of the patch electrode voltage clamp. The reversal potential of this current suggested that K+ was the primary charge carrier. The swelling-induced K+ current (IKvol) occurred in the absence of Ca2+ and was inhibited with 1 microM Ca2+ in the pipette solution. The activation of IKvol required both Mg2+ and ATP and an increasing concentration of Mg-ATP from 0.25 through 0.5 to 0.9 mM activated IKvol increasingly faster and to a larger extent. The KCNQ1 inhibitor chromanol 293B reversibly depressed IKvol with an IC50 of 26 microM. RT-PCR detected the expression of members of the KCNQ family from KCNQ1 to KCNQ5 and of the accessory proteins KCNE1 to KCNE3 in the rat hepatocytes, but not KCNQ2 and KCNE2 in human liver. Western blotting showed KCNE3 expression in a plasma membrane-enriched fraction from rat hepatocytes. The results suggest that KCNQ1, probably with KCNE2 or KCNE3 as its accessory unit, provides a significant fraction of IKvol in rat hepatocytes.

Amino Acid Sequence↗
PubMed2006

[Clinical and mutational analysis of KCNQ3 gene in a Chinese family with benign familial neonatal convulsions].

OBJECTIVE: To study the clinical and genetic characteristics of a Chinese family with benign familial convulsions (BFNC). METHODS: The clinical data of this family was analyzed. The blood samples were collected from 13 members of this family. By four microsatellite markers which are located in the gene loci of both K+ channel KCNQ2 and KCNQ3, the linkage analysis was performed in the family. With DNA direct sequencing and restriction endonuclease cutting analysis, the mutation analysis of KCNQ3 gene was made for the proband, other 12 family members and 76 unrelated normal individuals. RESULTS: There were 7 patients with BFNC observed in the three generation of family. The BFNC seizures of all patients disappeared during one month and no recurrence of seizures was found. The linkage analysis suggested the disease gene linked to KCNQ3 gene locus in the family. The mutation 988(C to T) of KCNQ3 gene was found in the proband by DNA-direct sequencing. Cosegregation of this mutation with BFNC was confirmed by restriction endonuclease cutting analysis. CONCLUSION: Chinese patients with BFNC can be caused by KCNQ3 gene mutation.

Base Sequence↗
PubMed2005

Protein kinase C shifts the voltage dependence of KCNQ/M channels expressed in Xenopus oocytes.

It is well established that stimulation of G(q)-coupled receptors such as the M1 muscarinic acetylcholine receptor inhibits KCNQ/M currents. While it is generally accepted that this muscarinic inhibition is mainly caused by the breakdown of PIP(2), the role of the subsequent activation of protein kinase C (PKC) is not well understood. By reconstituting M currents in Xenopus oocytes, we observed that stimulation of coexpressed M1 receptors with 10 microm oxotremorine M (oxo-M) induces a positive shift (4-30 mV, depending on which KCNQ channels are expressed) in the conductance-voltage relationship (G-V) of KCNQ channels. When we applied phorbol 12-myristate 13-acetate (PMA), a potent PKC activator, we observed a large positive shift (17.8 +/- 1.6 mV) in the G-V curve for KCNQ2, while chelerythrine, a PKC inhibitor, attenuated the shift caused by the stimulation of M1 receptors. By contrast, reducing PIP(2) had little effect on the G-V curve for KCNQ2 channels; although pretreating cells with 10 mum wortmannin for 30 min reduced KCNQ2 current amplitude by 80%, the G-V curve was shifted only slightly (5 mV). Apparently, the shift induced by muscarinic stimulation in Xenopus oocytes was mainly caused by PKC activation. When KCNQ2/3 channels were expressed in HEK 293T cells, the G-V curve seemed already to be shifted in a positive direction, even before activation of PKC, and PMA failed to shift the curve any further. That alkaline phosphatase in the patch pipette shifted the G-V curve in a negative direction suggests KCNQ2/3 channels are constitutively phosphorylated in HEK 293T cells.

Animals↗