Neuronal KCNQ potassium channels:physislogy and role in disease (original) (raw)
Related papers
Properties of single M-type KCNQ2/KCNQ3 potassium channels expressed in mammalian cells
The Journal of Physiology, 2001
KCNQ2 and KCNQ3 subunits form heteromeric potassium channels that underlie slow, subthreshold M-type potassium currents in autonomic (and possibly central) neurones (Wang et al. 1998). They are related to KCNQ1 (Yang et al. 1997) and KCNQ4 (Kubisch et al. 1999) subunits, mutations of which produce one form of the cardiac long QT syndrome and deafness, respectively. KCNQ2 and KCNQ3 subunits are expressed exclusively in the nervous system and their mutations produce a benign form of epilepsy in newborns (
M-type KCNQ2–KCNQ3 potassium channels are modulated by the KCNE2 subunit
FEBS Letters, 2000
KCNQ2 and KCNQ3 subunits belong to the six transmembrane domain K + channel family and loss of function mutations are associated with benign familial neonatal convulsions. KCNE2 (MirP1) is a single transmembrane domain subunit first described to be a modulator of the HERG potassium channel in the heart. Here, we show that KCNE2 is present in brain, in areas which also express KCNQ2 and KCNQ3 channels. We demonstrate that KCNE2 associates with KCNQ2 and/or KCNQ3 subunits. In transiently transfected COS cells, KCNE2 expression produces an acceleration of deactivation kinetics of KCNQ2 and of the KCNQ2^KCNQ3 complex. Effects of two previously identified arrhythmogenic mutations of KCNE2 have also been analyzed. ß
FEBS Letters, 1998
Benign familial neonatal convulsions, an autosomal dominant epilepsy of newborns, are linked to mutations affecting two six-transmembrane potassium channels, KCNQ2 and KCNQ3. We isolated four splice variants of KCNQ2 in human brain. Two forms generate, after transient expression in COS cells, a potassium-selective current similar to the KCNQ1 current. L-735,821, a benzodiazepine molecule which inhibits the KCNQ1 channel activity (EC SH = 0.08 W WM), also blocks KCNQ2 currents (EC SH = 1.5 W WM). Using in situ hybridization, KCNQ2 and KCNQ3 have been localized within the central nervous system, in which they are expressed in the same areas, mainly in the hippocampus, the neocortex and the cerebellar cortex. During brain development, KCNQ3 is expressed later than KCNQ2.
Pharmacological Activation of Normal and Arrhythmia-Associated Mutant KCNQ1 Potassium Channels
Circulation Research, 2003
KCNQ1 alpha-subunits coassemble with KCNE1 beta-subunits to form channels that conduct the slow delayed rectifier K+ current (IKs) important for repolarization of the cardiac action potential. Mutations in KCNQ1 reduce IKs and cause long-QT syndrome, a disorder of ventricular repolarization that predisposes affected individuals to arrhythmia and sudden death. Current therapy for long-QT syndrome is inadequate. R-L3 is a benzodiazepine that activates IKs and has the potential to provide gene-specific therapy. In the present study, we characterize the molecular determinants of R-L3 interaction with KCNQ1 channels, use computer modeling to propose a mechanism for drug-induced changes in channel gating, and determine its effect on several long-QT syndrome-associated mutant KCNQ1 channels heterologously expressed in Xenopus oocytes. Scanning mutagenesis combined with voltage-clamp analysis indicated that R-L3 interacts with specific residues located in the 5th and 6th transmembrane domains of KCNQ1 subunits. Most KCNQ1 mutant channels responded to R-L3 similarly to wild-type channels, but one mutant channel (G306R) was insensitive to R-L3 possibly because it disrupted a key component of the drug-binding site.
KCNQ2 and KCNQ3 Potassium Channel Subunits: Molecular Correlates of the M-Channel
Science
The M-current regulates the subthreshold electrical excitability of many neurons, determining their firing properties and responsiveness to synaptic input. To date, however, the genes that encode subunits of this important channel have not been identified. 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. The M-current is a slowly activating and deactivating potassium conductance that plays a critical role in determining the subthreshold electrical excitability of neurons as well as the responsiveness to synaptic inputs (1-3). The M-current was first described in peripheral sympathetic neurons (4, 5), and differential expression of this conductance produces subtypes of sympathetic neurons with distinct firing patterns (3). The M-current is also expressed in many neurons in the central nervous system (CNS) (1, 6, 7). To date, the molecular identity of the channels underlying the M-current remains unknown. Here we show that the KCNQ2 and KCNQ3 channel subunits can coassemble to form a channel with essentially identical biophysical properties and pharmacological sensitivities to the native M-current and that the pattern of KCNQ2 and KCNQ3 gene expression is consistent with these genes encoding the native M-current. The KCNQ potassium channel gene family has three members: KCNQ1 (KvLQT1), KCNQ2, and KCNQ3 (8-12). Injection of KCNQ2 mRNA into Xenopus oocytes resulted in the consistent expression of a relatively small potassium current that is slowly activating and deactivating (Fig. 1A). The properties of this channel are essentially identical to those described previously (11). In contrast, injection of KCNQ3 mRNA did not result in the expression of a current above background level. When the KCNQ2 and KCNQ3 mRNAs were coinjected, however, the resultant current was 11-fold larger than
Annals of Neurology, 2000
Episodic ataxia type 1 (EA1) is an autosomal dominant central nervous system potassium channelopathy characterized by brief attacks of cerebellar ataxia and continuous interictal myokymia. Point mutations in the voltage-gated potassium channel gene KCNA1 on chromosome 12p associate with EA1. We have studied 4 families and identified three new and one previously reported heterozygous point mutations in this gene. Affected members in Family A (KCNA1 G724C) exhibit partial epilepsy and myokymia but no ataxic episodes, supporting the suggestion that there is an association between mutations of KCNA1 and epilepsy. Affected members in Family B (KCNA1 C731A) exhibit myokymia alone, suggesting a new phenotype of isolated myokymia. Family C harbors the first truncation to be reported in KCNA1 (C1249T) and exhibits remarkably drug-resistant EA1. Affected members in Family D (KCNA1 G1210A) exhibit attacks typical of EA1. This mutation has recently been reported in an apparently unrelated family, although no functional studies were attempted. Heterologous expression of the proteins encoded by the mutant KCNA1 genes suggest that the four point mutations impair delayed-rectifier type potassium currents by different mechanisms. Increased neuronal excitability is likely to be the common pathophysiological basis for the disease in these families. The degree and nature of the potassium channel dysfunction may be relevant to the new phenotypic observations reported in this study.
Biochemistry, 2007
KCNE1, also known as minK, is a member of the KCNE family of membrane proteins that modulate the function of KCNQ1 and certain other voltage-gated potassium channels (K V ). Mutations in human KCNE1 cause congenital deafness and congenital long QT syndrome, an inherited predisposition to potentially life-threatening cardiac arrhythmias. Although its modulation of KCNQ1 function has been extensively characterized, many questions remain regarding KCNE1's structure and location within the channel complex. In this study KCNE1 was overexpressed in E. coli and purified. Micellar solutions of the protein were then microinjected into Xenopus oocytes expressing KCNQ1 channels, followed by electrophysiological recordings to test whether recombinant KCNE1 can co-assemble with the channel. Native-like modulation of channel properties was observed following injection of KCNE1 in lysomyristoylphosphatidylglycerol (LMPG) micelles, indicating that KCNE1 is not irreversibly misfolded and that LMPG is able to act as a vehicle for delivering membrane proteins into the membranes of viable cells. 1 H, 15 N-TROSY NMR experiments indicated that LMPG micelles are well-suited for structural studies of KCNE1, leading to assignment of its backbone resonances and to relaxation studies. The chemical shift data confirmed that KCNE1's secondary structure includes several α-helices and demonstrated that its distal Cterminus is disordered. Surprisingly, for KCNE1 in LMPG micelles there appears to be a break in α-helicity at sites 59−61, near the middle of the transmembrane segment, a feature that is accompanied by increased local backbone mobility. Given that this segment overlaps with sites 57 −59, which are known to play a critical role in modulating KCNQ1 channel activation kinetics, this unusual structural feature is likely of considerable functional relevance.
Canadian Journal of Physiology and Pharmacology, 2003
The congenital long QT syndrome (LQTS) is a hereditary cardiac disease characterized by prolonged ventricular repolarization, syncope, and sudden death. Mutations causing LQTS have been identified in various genes that encode for ionic channels or their regulatory subunits. Several of these mutations have been reported on the KCNQ1 gene encoding for a potassium channel or its regulatory subunit (KCNE1). In this study, we report the biophysical characteristics of a new mutation (L251P) in the transmembrane segment 5 (S5) of the KCNQ1 potassium channel. Potassium currents were recorded from CHO cells transfected with either wild type or mutant KCNQ1 in the presence or in the absence of its regulatory subunit (KCNE1), using the whole-cell configuration of the patch clamp technique. Wild-type KCNQ1 current amplitudes are increased particularly by KCNE1 co-expression but no current is observed with the KCNQ1 (L251P) mutant either in the presence or in the absence of KCNE1. Coexpressing K...
Journal of Neuroscience, 2007
Heteromeric assembly of KCNQ2 and KCNQ3 subunits underlie the M-current (I KM ), a slowly activating and noninactivating neuronal K ϩ current. Mutations in KCNQ2 and KCNQ3 genes cause benign familial neonatal convulsions (BFNCs), a rare autosomal-dominant epilepsy of the newborn. In the present study, we describe the identification of a novel KCNQ2 heterozygous mutation (c587t) in a BFNC-affected family, leading to an alanine to valine substitution at amino acid position 196 located at the N-terminal end of the voltage-sensing S 4 domain. The consequences on KCNQ2 subunit function prompted by the A196V substitution, as well as by the A196V/L197P mutation previously described in another BFNC-affected family, were investigated by macroscopic and single-channel current measurements in CHO cells transiently transfected with wild-type and mutant subunits. When compared with KCNQ2 channels, homomeric KCNQ2 A196V or A196V/L197P channels showed a 20 mV rightward shift in their activation voltage dependence, with no concomitant change in maximal open probability or single-channel conductance. Furthermore, current activation kinetics of KCNQ2 A196V channels displayed an unusual dependence on the conditioning prepulse voltage, being markedly slower when preceded by prepulses to more depolarized potentials. Heteromeric channels formed by KCNQ2 A196V and KCNQ3 subunits displayed gating changes similar to those of KCNQ2 A196V homomeric channels. Collectively, these results reveal a novel role for noncharged residues in the N-terminal end of S 4 in controlling gating of I KM and suggest that gating changes caused by mutations at these residues may decrease I KM function, thus causing neuronal hyperexcitability, ultimately leading to neonatal convulsions.
Structure of KCNE1 and Implications for How It Modulates the KCNQ1 Potassium Channel † ‡
Biochemistry, 2008
KCNE1 is a single span membrane protein that modulates the voltage-gated potassium channel KCNQ1 (K V 7.1) by slowing activation and enhancing channel conductance to generate the slow delayed rectifier current (I Ks ) that is critical for the repolarization phase of the cardiac action potential. Perturbation of channel function by inherited mutations in KCNE1 or KCNQ1 results in increased susceptibility to cardiac arrhythmias and sudden death with or without accompanying deafness. Here, we present the three-dimensional structure of KCNE1. The transmembrane domain (TMD) of KCNE1 is a curved α-helix and is flanked by intra-and extracellular domains comprised of α-helices joined by flexible linkers. Experimentally-restrained docking of the KCNE1 TMD to a closed state model of KCNQ1 suggests that KCNE1 slows channel activation by sitting on and restricting the movement of the S4-S5 linker that connects the voltage sensor to the pore domain. We postulate that this is an adhesive interaction that must be disrupted before the channel can be opened in response to membrane depolarization. Docking to open KCNQ1 indicates that the extracellular end of the KCNE1 TMD forms an interface with an intersubunit cleft in the channel that is associated with most known gain-of-function disease mutations. Binding of KCNE1 to this "gain-of-function cleft" may explain how it increases conductance and stabilizes the open state. These working models for the KCNE1/KCNQ1 complexes may be used to formulate testable hypotheses for the molecular bases of disease phenotypes associated with the dozens of known inherited mutations in KCNE1 and KCNQ1.