Genomes and Genes
kcnq2 potassium channel
Summary: A very slow opening and closing voltage-gated potassium channel that is expressed in NEURONS and is commonly mutated in BENIGN FAMILIAL NEONATAL CONVULSIONS.
- Hernandez C, Falkenburger B, Shapiro M. Affinity for phosphatidylinositol 4,5-bisphosphate determines muscarinic agonist sensitivity of Kv7 K+ channels. J Gen Physiol. 2009;134:437-48 pubmed publisher..We were able to fully reproduce our data and extract a consistent set of PIP(2) affinities. ..
- Dedek K, Fusco L, Teloy N, Steinlein O. Neonatal convulsions and epileptic encephalopathy in an Italian family with a missense mutation in the fifth transmembrane region of KCNQ2. Epilepsy Res. 2003;54:21-7 pubmed..Additional studies are needed to evaluate the possibility of a causal relationship between KCNQ2 mutations and severe early infantile epilepsy. ..
- Schwarz J, Glassmeier G, Cooper E, Kao T, Nodera H, Tabuena D, et al. KCNQ channels mediate IKs, a slow K+ current regulating excitability in the rat node of Ranvier. J Physiol. 2006;573:17-34 pubmed..We conclude that the nodal I(Ks) current is mediated by KCNQ channels, which in large fibres of rat sciatic nerve appear to be KCNQ2 homomers. ..
- Schwake M, Athanasiadu D, Beimgraben C, Blanz J, Beck C, Jentsch T, et al. Structural determinants of M-type KCNQ (Kv7) K+ channel assembly. J Neurosci. 2006;26:3757-66 pubmed
- Murata Y, Okamura Y. Depolarization activates the phosphoinositide phosphatase Ci-VSP, as detected in Xenopus oocytes coexpressing sensors of PIP2. J Physiol. 2007;583:875-89 pubmed publisher..These results indicate that Ci-VSP has an activity that depletes PtdIns(4,5)P(2) unlike PTEN and that depolarization-activated voltage sensor movement is translated into activation of phosphatase activity...
- Etzioni A, Siloni S, Chikvashvilli D, Strulovich R, Sachyani D, Regev N, et al. Regulation of neuronal M-channel gating in an isoform-specific manner: functional interplay between calmodulin and syntaxin 1A. J Neurosci. 2011;31:14158-71 pubmed publisher..Moreover, we show that the syntaxin 1A and calmodulin effects can be additive or blocked at different concentration ranges of calmodulin, bearing physiological significance with regard to presynaptic exocytosis. ..
- Jentsch T. Neuronal KCNQ potassium channels: physiology and role in disease. Nat Rev Neurosci. 2000;1:21-30 pubmed..In addition, several KCNQ isoforms can associate to form heteromeric channels that underlie the M-current, an important regulator of neuronal excitability. ..
- Pan Z, Selyanko A, Hadley J, Brown D, Dixon J, McKinnon D. Alternative splicing of KCNQ2 potassium channel transcripts contributes to the functional diversity of M-currents. J Physiol. 2001;531:347-58 pubmedThe region of alternative splicing in the KCNQ2 potassium channel gene was determined by RNase protection analysis of KCNQ2 mRNA transcripts...
- Kosenko A, Kang S, Smith I, Greene D, Langeberg L, Scott J, et al. Coordinated signal integration at the M-type potassium channel upon muscarinic stimulation. EMBO J. 2012;31:3147-56 pubmed publisher..This pathway enhances the effect of concomitant reduction of PIP2, which leads to disruption of the M-channel function. These findings clarify how a common lipid cofactor, such as PIP2, can selectively regulate ion channels. ..
- Smith J, Iannotti C, Dargis P, Christian E, Aiyar J. Differential expression of kcnq2 splice variants: implications to m current function during neuronal development. J Neurosci. 2001;21:1096-103 pubmed
- Yus Najera E, Santana Castro I, Villarroel A. The identification and characterization of a noncontinuous calmodulin-binding site in noninactivating voltage-dependent KCNQ potassium channels. J Biol Chem. 2002;277:28545-53 pubmed..Thus, we propose that CaM acts as a mediator in the Ca2+-dependent modulation of KCNQ channels. ..
- Singh N, Westenskow P, Charlier C, Pappas C, Leslie J, Dillon J, et al. KCNQ2 and KCNQ3 potassium channel genes in benign familial neonatal convulsions: expansion of the functional and mutation spectrum. Brain. 2003;126:2726-37 pubmed..We report here the first dominant negative mutation in KCNQ2 that has a phenotype of neonatal seizures without permanent clinical CNS impairment. ..
- Falkenburger B, Dickson E, Hille B. Quantitative properties and receptor reserve of the DAG and PKC branch of G(q)-coupled receptor signaling. J Gen Physiol. 2013;141:537-55 pubmed publisher..Finally, our experimental data provide indirect evidence for cleavage of PI(4)P by PLC in living cells, and our modeling revisits/explains the concept of receptor reserve with measurements from all steps of GqPCR signaling. ..
- Li Y, Gamper N, Shapiro M. Single-channel analysis of KCNQ K+ channels reveals the mechanism of augmentation by a cysteine-modifying reagent. J Neurosci. 2004;24:5079-90 pubmed..To further localize the site of NEM action, we mutated three cysteine residues in the C terminus of KCNQ4. The C519A mutation alone ablated most of the augmentation by NEM, suggesting that NEM acts via alkylation of this residue. ..
- Cheung Y, Yu H, Xu K, Zou B, Wu M, McManus O, et al. Discovery of a series of 2-phenyl-N-(2-(pyrrolidin-1-yl)phenyl)acetamides as novel molecular switches that modulate modes of K(v)7.2 (KCNQ2) channel pharmacology: identification of (S)-2-phenyl-N-(2-(pyrrolidin-1-yl)phenyl)butanamide (ML252) as a pot. J Med Chem. 2012;55:6975-9 pubmed publisher
- Schwake M, Pusch M, Kharkovets T, Jentsch T. Surface expression and single channel properties of KCNQ2/KCNQ3, M-type K+ channels involved in epilepsy. J Biol Chem. 2000;275:13343-8 pubmed..Thus, the increase in currents seen upon co-expressing KCNQ2 and KCNQ3 is predominantly due to an increase in surface expression, which is dependent on an intact carboxyl terminus. ..
- Devaux J, Kleopa K, Cooper E, Scherer S. KCNQ2 is a nodal K+ channel. J Neurosci. 2004;24:1236-44 pubmed..The diminished activity of mutant KCNQ2 channels accounts for neonatal epilepsy and myokymia; the cellular locus of these effects may be axonal initial segments and nodes...
- Brown D, Hughes S, Marsh S, Tinker A. Regulation of M(Kv7.2/7.3) channels in neurons by PIP(2) and products of PIP(2) hydrolysis: significance for receptor-mediated inhibition. J Physiol. 2007;582:917-25 pubmed..Thus, inhibition by bradykinin can use product (IP(3)/Ca(2)+)-dependent or substrate (PIP(2)) dependent mechanisms, depending on Ca(2)+ availability and PIP(2) synthesis rates. ..
- Martire M, D Amico M, Panza E, Miceli F, Viggiano D, Lavergata F, et al. Involvement of KCNQ2 subunits in [3H]dopamine release triggered by depolarization and pre-synaptic muscarinic receptor activation from rat striatal synaptosomes. J Neurochem. 2007;102:179-93 pubmed
- Gamper N, Shapiro M. Calmodulin mediates Ca2+-dependent modulation of M-type K+ channels. J Gen Physiol. 2003;122:17-31 pubmed..We conclude that M-type currents are highly sensitive to [Ca2+]i and that calmodulin acts as their Ca2+ sensor. ..
- Maljevic S, Lerche C, Seebohm G, Alekov A, Busch A, Lerche H. C-terminal interaction of KCNQ2 and KCNQ3 K+ channels. J Physiol. 2003;548:353-60 pubmed..Our results indicate that specific parts of the C-terminus enable the interaction between KCNQ2 and KCNQ3 channels and that different parts of the KCNQ3 C-terminus are important for regulating current amplitude. ..
- Wladyka C, Kunze D. KCNQ/M-currents contribute to the resting membrane potential in rat visceral sensory neurons. J Physiol. 2006;575:175-89 pubmed..These data indicate that the M-current is present in nodose neurons, is activated at resting membrane potential and that it is physiologically important in regulating excitability by maintaining cells at negative voltages. ..
- Hunter J, Maljevic S, Shankar A, Siegel A, Weissman B, Holt P, et al. Subthreshold changes of voltage-dependent activation of the K(V)7.2 channel in neonatal epilepsy. Neurobiol Dis. 2006;24:194-201 pubmed..2 S2 segment in voltage-dependent channel gating and demonstrate in a human disease that subthreshold voltages are likely to represent the physiologically relevant range for this K+ channel to regulate neuronal firing. ..
- Wu Y, He H, Sun L, L Heureux A, Chen J, Dextraze P, et al. Synthesis and structure-activity relationship of acrylamides as KCNQ2 potassium channel openers. J Med Chem. 2004;47:2887-96 pubmed..These two acrylamides demonstrated significant activity in the cortical spreading depression model of migraine as we reported previously. ..
- Pan Z, Kao T, Horvath Z, Lemos J, Sul J, Cranstoun S, et al. A common ankyrin-G-based mechanism retains KCNQ and NaV channels at electrically active domains of the axon. J Neurosci. 2006;26:2599-613 pubmed..This includes the historical period when myelin also evolved. ..
- Shahidullah M, Santarelli L, Wen H, Levitan I. Expression of a calmodulin-binding KCNQ2 potassium channel fragment modulates neuronal M-current and membrane excitability. Proc Natl Acad Sci U S A. 2005;102:16454-9 pubmed..These results suggest that CaM binding regulates M-channel function and membrane excitability in the native neuronal environment. ..
- Shah M, Mistry M, Marsh S, Brown D, Delmas P. Molecular correlates of the M-current in cultured rat hippocampal neurons. J Physiol. 2002;544:29-37 pubmed..Our data suggest that KCNQ2, KCNQ3 and KCNQ5 subunits contribute to I(K(M)) in these neurons and that the variations in TEA sensitivity may reflect differential expression of KCNQ2, KCNQ3 and KCNQ5 subunits. ..
- Borgatti R, Zucca C, Cavallini A, Ferrario M, Panzeri C, Castaldo P, et al. A novel mutation in KCNQ2 associated with BFNC, drug resistant epilepsy, and mental retardation. Neurology. 2004;63:57-65 pubmed..Genetic rather than acquired factors may be involved in the pathophysiology of the phenotypic variability of the neurologic symptoms associated with BFNC in the described family. ..
- Peters H, Hu H, Pongs O, Storm J, Isbrandt D. Conditional transgenic suppression of M channels in mouse brain reveals functions in neuronal excitability, resonance and behavior. Nat Neurosci. 2005;8:51-60 pubmed..M channels are thus critical determinants of cellular and neuronal network excitability, postnatal brain development and cognitive performance. ..
- Wang H, Pan Z, Shi W, Brown B, Wymore R, Cohen I, et al. KCNQ2 and KCNQ3 potassium channel subunits: molecular correlates of the M-channel. Science. 1998;282:1890-3 pubmed..The biophysical properties, sensitivity to pharmacological blockade, and expression pattern of the KCNQ2 and KCNQ3 potassium channels were determined. It is concluded that both these subunits contribute to the native M-current. ..
- Dost R, Rostock A, Rundfeldt C. The anti-hyperalgesic activity of retigabine is mediated by KCNQ potassium channel activation. Naunyn Schmiedebergs Arch Pharmacol. 2004;369:382-90 pubmed..Since the anti-allodynic effect can be inhibited by linopirdine we can conclude that the potassium channel opening properties of retigabine are critically involved in its ability to reduce neuropathic pain response...
- Suh B, Inoue T, Meyer T, Hille B. Rapid chemically induced changes of PtdIns(4,5)P2 gate KCNQ ion channels. Science. 2006;314:1454-7 pubmed..Hence, the depletion of PI(4,5)P2 suffices to suppress current fully, and other second messengers are not needed. Our approach is ideally suited to study biological signaling networks involving membrane phosphoinositides. ..
- Hadley J, Passmore G, Tatulian L, Al Qatari M, Ye F, Wickenden A, et al. Stoichiometry of expressed KCNQ2/KCNQ3 potassium channels and subunit composition of native ganglionic M channels deduced from block by tetraethylammonium. J Neurosci. 2003;23:5012-9 pubmed
- Coppola G, Castaldo P, Miraglia del Giudice E, Bellini G, Galasso F, Soldovieri M, et al. A novel KCNQ2 K+ channel mutation in benign neonatal convulsions and centrotemporal spikes. Neurology. 2003;61:131-4 pubmed..Electrophysiologic studies showed that mutant K+ channel subunits failed to give rise to functional homomeric channels or exert dominant-negative effects when expressed with KCNQ2/KCNQ3 subunits. ..
- Yang W, Levesque P, Little W, Conder M, Ramakrishnan P, Neubauer M, et al. Functional expression of two KvLQT1-related potassium channels responsible for an inherited idiopathic epilepsy. J Biol Chem. 1998;273:19419-23 pubmed..The functional interaction between KCNQ2 and KCNQ3 provides a framework for understanding how mutations in either channel can cause a form of idiopathic generalized epilepsy. ..
- Cooper E, Harrington E, Jan Y, Jan L. M channel KCNQ2 subunits are localized to key sites for control of neuronal network oscillations and synchronization in mouse brain. J Neurosci. 2001;21:9529-40 pubmed..There is strong neuropil staining in many regions. In some instances, notably the hippocampal mossy fibers, evidence indicates this neuropil staining is presynaptic. ..
- Zhang H, Craciun L, Mirshahi T, Rohacs T, Lopes C, Jin T, et al. PIP(2) activates KCNQ channels, and its hydrolysis underlies receptor-mediated inhibition of M currents. Neuron. 2003;37:963-75 pubmed..Finally, native or recombinant channels inhibited by muscarinic agonists can be activated by PIP(2). Our data strongly suggest that PIP(2) acts as a membrane-diffusible second messenger to regulate directly the activity of KCNQ currents...
- Jensen J, Lyssand J, Hague C, Hille B. Fluorescence changes reveal kinetic steps of muscarinic receptor-mediated modulation of phosphoinositides and Kv7.2/7.3 K+ channels. J Gen Physiol. 2009;133:347-59 pubmed publisher..0 s) to become nearly contemporaneous with Galpha(q)/PLC interaction. Evidently, channel release of PIP(2) and closure are rapid, and the availability of active PLC limits the rate of M current suppression. ..
- Martire M, Castaldo P, D Amico M, Preziosi P, Annunziato L, Taglialatela M. M channels containing KCNQ2 subunits modulate norepinephrine, aspartate, and GABA release from hippocampal nerve terminals. J Neurosci. 2004;24:592-7 pubmed..These findings provide novel evidence for a major regulatory role of KCNQ2 K+ channel subunits in neurotransmitter release from rat hippocampal nerve endings...
- Chung H, Jan Y, Jan L. Polarized axonal surface expression of neuronal KCNQ channels is mediated by multiple signals in the KCNQ2 and KCNQ3 C-terminal domains. Proc Natl Acad Sci U S A. 2006;103:8870-5 pubmed..We further show that several BFNC mutations of KCNQ2 and KCNQ3 disrupt surface expression or polarized surface distribution of KCNQ channels, thereby revealing impaired targeting of KCNQ channels to axonal surfaces as a BFNC etiology. ..
- Singh N, Charlier C, Stauffer D, DuPont B, Leach R, Melis R, et al. A novel potassium channel gene, KCNQ2, is mutated in an inherited epilepsy of newborns. Nat Genet. 1998;18:25-9 pubmed..This finding in BFNC provides additional evidence that defects in potassium channels are involved in the mammalian epilepsy phenotype. ..
- Yus Najera E, Munoz A, Salvador N, Jensen B, Rasmussen H, Defelipe J, et al. Localization of KCNQ5 in the normal and epileptic human temporal neocortex and hippocampal formation. Neuroscience. 2003;120:353-64 pubmed
- Cooper E, Jan L. M-channels: neurological diseases, neuromodulation, and drug development. Arch Neurol. 2003;60:496-500 pubmed..Ongoing studies in humans and animal models will refine our understanding of KCNQ channel function and may reveal additional targets for therapeutic manipulation. ..
- Prole D, Lima P, Marrion N. Mechanisms underlying modulation of neuronal KCNQ2/KCNQ3 potassium channels by extracellular protons. J Gen Physiol. 2003;122:775-93 pubmed..Contrasting modulation of homomeric KCNQ2 and KCNQ3 currents revealed that high sensitivity to H+ ions was conferred by the KCNQ3 subunit. ..
- Mucha M, Ooi L, Linley J, Mordaka P, Dalle C, Robertson B, et al. Transcriptional control of KCNQ channel genes and the regulation of neuronal excitability. J Neurosci. 2010;30:13235-45 pubmed publisher..We propose that these mechanisms are important in the control of excitability of neurons and may have implications in seizure activity and pain. ..
- Watanabe H, Nagata E, Kosakai A, Nakamura M, Yokoyama M, Tanaka K, et al. Disruption of the epilepsy KCNQ2 gene results in neural hyperexcitability. J Neurochem. 2000;75:28-33 pubmed..These data indicate that the decreased expression of KCNQ2 might cause a hyperexcitability of the CNS, which accounts for the mechanism of BFNC. ..
- Miceli F, Soldovieri M, Ambrosino P, Barrese V, Migliore M, Cilio M, et al. Genotype-phenotype correlations in neonatal epilepsies caused by mutations in the voltage sensor of K(v)7.2 potassium channel subunits. Proc Natl Acad Sci U S A. 2013;110:4386-91 pubmed publisher..2 encephalopathy. ..
- Suh B, Horowitz L, Hirdes W, Mackie K, Hille B. Regulation of KCNQ2/KCNQ3 current by G protein cycling: the kinetics of receptor-mediated signaling by Gq. J Gen Physiol. 2004;123:663-83 pubmed..Further experiments will be needed to refine some untested assumptions. ..
- Loussouarn G, Park K, Bellocq C, Baro I, Charpentier F, Escande D. Phosphatidylinositol-4,5-bisphosphate, PIP2, controls KCNQ1/KCNE1 voltage-gated potassium channels: a functional homology between voltage-gated and inward rectifier K+ channels. EMBO J. 2003;22:5412-21 pubmed..Our data suggest a striking functional homology between a six transmembrane-domain voltage-gated channel and a two transmembrane-domain ATP-gated channel. ..
- Gómez Posada J, Aivar P, Alberdi A, Alaimo A, Etxeberria A, Fernandez Orth J, et al. Kv7 channels can function without constitutive calmodulin tethering. PLoS ONE. 2011;6:e25508 pubmed publisher..However, we have identified a presumably phosphomimetic mutation S511D that permits calmodulin-independent function. Thus, our data reveal that constitutive tethering of calmodulin is not required for Kv7 channel function. ..
- Saganich M, Machado E, Rudy B. Differential expression of genes encoding subthreshold-operating voltage-gated K+ channels in brain. J Neurosci. 2001;21:4609-24 pubmed..This indicates that the subthreshold current in many neurons may be complex, containing different components mediated by a number of channels with distinct properties and neuromodulatory responses. ..