Kv7 channels can function without constitutive calmodulin tethering.
Ontology highlight
ABSTRACT:
SUBMITTER: Gomez-Posada JC
PROVIDER: S-EPMC3182250 | biostudies-literature | 2011
REPOSITORIES: biostudies-literature
Publications
Kv7 channels can function without constitutive calmodulin tethering.
Gómez-Posada Juan Camilo JC Aivar Paloma P Alberdi Araitz A Alaimo Alessandro A Etxeberría Ainhoa A Fernández-Orth Juncal J Zamalloa Teresa T Roura-Ferrer Meritxell M Villace Patricia P Areso Pilar P Casis Oscar O Villarroel Alvaro A
PloS one 20110928 9
M-channels are voltage-gated potassium channels composed of Kv7.2-7.5 subunits that serve as important regulators of neuronal excitability. Calmodulin binding is required for Kv7 channel function and mutations in Kv7.2 that disrupt calmodulin binding cause Benign Familial Neonatal Convulsions (BFNC), a dominantly inherited human epilepsy. On the basis that Kv7.2 mutants deficient in calmodulin binding are not functional, calmodulin has been defined as an auxiliary subunit of Kv7 channels. Howeve ...[more]
Similar Datasets
Project description:Kv7 (KCNQ) voltage-gated potassium channels control excitability in the brain, heart, and ear. Calmodulin (CaM) is crucial for Kv7 function, but how this calcium sensor affects activity has remained unclear. Here, we present X-ray crystallographic analysis of CaM:Kv7.4 and CaM:Kv7.5 AB domain complexes that reveal an Apo/CaM clamp conformation and calcium binding preferences. These structures, combined with small-angle X-ray scattering, biochemical, and functional studies, establish a regulatory mechanism for Kv7 CaM modulation based on a common architecture in which a CaM C-lobe calcium-dependent switch releases a shared Apo/CaM clamp conformation. This C-lobe switch inhibits voltage-dependent activation of Kv7.4 and Kv7.5 but facilitates Kv7.1, demonstrating that mechanism is shared by Kv7 isoforms despite the different directions of CaM modulation. Our findings provide a unified framework for understanding how CaM controls different Kv7 isoforms and highlight the role of membrane proximal domains for controlling voltage-gated channel function. VIDEO ABSTRACT.
| S-EPMC5823783 | biostudies-literature
Project description:Lung diseases constitute a global health concern causing disability. According to WHO in 2016, respiratory diseases accounted for 24% of world population mortality, the second cause of death after cardiovascular diseases. The Kv7 channels family is a group of voltage-dependent K+ channels (Kv) encoded by KCNQ genes that are involved in various physiological functions in numerous cell types, especially, cardiac myocytes, smooth muscle cells, neurons, and epithelial cells. Kv7 channel α-subunits are regulated by KCNE1-5 ancillary β-subunits, which modulate several characteristics of Kv7 channels such as biophysical properties, cell-location, channel trafficking, and pharmacological sensitivity. Kv7 channels are mainly expressed in two large groups of lung tissues: pulmonary arteries (PAs) and bronchial tubes. In PA, Kv7 channels are expressed in pulmonary artery smooth muscle cells (PASMCs); while in the airway (trachea, bronchus, and bronchioles), Kv7 channels are expressed in airway smooth muscle cells (ASMCs), airway epithelial cells (AEPs), and vagal airway C-fibers (VACFs). The functional role of Kv7 channels may vary depending on the cell type. Several studies have demonstrated that the impairment of Kv7 channel has a strong impact on pulmonary physiology contributing to the pathophysiology of different respiratory diseases such as cystic fibrosis, asthma, chronic obstructive pulmonary disease, chronic coughing, lung cancer, and pulmonary hypertension. Kv7 channels are now recognized as playing relevant physiological roles in many tissues, which have encouraged the search for Kv7 channel modulators with potential therapeutic use in many diseases including those affecting the lung. Modulation of Kv7 channels has been proposed to provide beneficial effects in a number of lung conditions. Therefore, Kv7 channel openers/enhancers or drugs acting partly through these channels have been proposed as bronchodilators, expectorants, antitussives, chemotherapeutics and pulmonary vasodilators.
| S-EPMC7333540 | biostudies-literature
Project description:Relaxation and contraction of the urinary bladder smooth muscle, also known as the detrusor smooth muscle (DSM), facilitate the micturition cycle. DSM contractility depends on cell excitability, which is established by the synchronized activity of multiple diverse ion channels. K+ channels, the largest family of channels, control DSM excitability by maintaining the resting membrane potential and shaping the action potentials that cause the phasic contractions. Among the members of the voltage-gated K+ (KV) channel superfamily, KV type 7 (KV7) channels — KV7.1–KV7.5 members encoded by KCNQ1–KCNQ5 genes — have been recently identified as functional regulators in various cell types including vascular, cardiac, and neuronal cells. Their regulatory roles in DSM, however, are just now emerging and remain to be elucidated. To address this gap, our research group has initiated the systematic investigation of human DSM KV7 channels in collaboration with clinical urologists. In this comprehensive review, we summarize the current understanding of DSM Kv7 channels and highlight recent discoveries in the field. We describe KV7 channel expression profiles at the mRNA and protein levels, and further elaborate on functional effects of KV7 channel selective modulators on DSM excitability, contractility, and intracellular Ca2+ dynamics in animal species along with in vivo studies and the limited data on human DSM. Within each topic, we highlight the main observations, current gaps in knowledge, and most pressing questions and concepts in need of resolution. We emphasize the lack of systematic studies on human DSM KV7 channels that are now actively ongoing in our laboratory.
| S-EPMC7526500 | biostudies-literature
Project description:The rising interest in Kv7 modulators originates from their ability to evoke fundamental electrophysiological perturbations in a tissue-specific manner. A large number of therapeutic applications are, in part, based on the clinical experience with two broad-spectrum Kv7 agonists, flupirtine and retigabine. Since precise molecular structures of human Kv7 channel subtypes in closed and open states have only very recently started to emerge, computational studies have traditionally been used to analyze binding modes and direct the development of more potent and selective Kv7 modulators with improved safety profiles. Herein, the synthetic and medicinal chemistry of small molecule modulators and the representative biological properties are summarized. Furthermore, new therapeutic applications supported by in vitro and in vivo assay data are suggested.
| S-EPMC8128042 | biostudies-literature
Project description:Voltage-gated K+ channels are dynamic macromolecular machines that open and close in response to changes in membrane potential. These multisubunit membrane-embedded proteins are responsible for governing neuronal excitability, maintaining cardiac rhythmicity, and regulating epithelial electrolyte homeostasis. High resolution crystal structures have provided snapshots of K+ channels caught in different states with incriminating molecular detail. Nonetheless, the connection between these static images and the specific trajectories of K+ channel movements is still being resolved by biochemical experimentation. Electrophysiological recordings in the presence of chemical modifying reagents have been a staple in ion channel structure/function studies during both the pre- and post-crystal structure eras. Small molecule tethering agents (chemoselective electrophiles linked to ligands) have proven to be particularly useful tools for defining the architecture and motions of K+ channels. This Minireview examines the synthesis and utilization of chemical tethering agents to probe and manipulate the assembly, structure, function, and molecular movements of voltage-gated K+ channel protein complexes.
| S-EPMC2533090 | biostudies-literature
Project description:Skin keratinocytes fulfil important signalling and protective functions. Immunocytochemical experiments revealed the unexpected presence of immunoreactivity for the M-type potassium channel subunit Kv7.2 in the keratinocyte layer of intact rat paw skin and in keratinocytes isolated from the skin of 1-day-old rats and cultured in vitro for 3-10 days. Application of the M-channel enhancer retigabine (3-10 μM) to isolated cultured rat keratinocytes: (a) increased outward membrane currents recorded under voltage clamp, (b) produced ~3 mV hyperpolarization at rest, (c) enhanced ~3-fold the release of ATP induced by the TRPV3 agonist carvacrol (1 mM) and (d) increased the amplitude of the carvacrol-induced intracellular Ca(2+) transient measured with Fura-2. The effect of retigabine on ATP release was prevented by the M-channel blocking agent XE991. We conclude that rat skin keratinocytes possess M-channels that, when activated, can modify their physiological properties, with potential significance for their sensory and other biological functions.
| S-EPMC3745621 | biostudies-literature
Project description:Members of the Kv7 family (Kv7.2-Kv7.5) generate a subthreshold K(+) current, the M- current. This regulates the excitability of many peripheral and central neurons. Recent evidence shows that Kv7.2 and Kv7.3 subunits are targeted to the axon initial segment of hippocampal neurons by association with ankyrin G. Further, spontaneous mutations in these subunits that impair axonal targeting cause human neonatal epilepsy. However, the precise functional significance of their axonal location is unknown. Using electrophysiological techniques together with a peptide that selectively disrupts axonal Kv7 targeting (ankyrin G-binding peptide, or ABP) and other pharmacological tools, we show that axonal Kv7 channels are critically and uniquely required for determining the inherent spontaneous firing of hippocampal CA1 pyramids, independently of alterations in synaptic activity. This action was primarily because of modulation of action potential threshold and resting membrane potential (RMP), amplified by control of intrinsic axosomatic membrane properties. Computer simulations verified these data when the axonal Kv7 density was three to five times that at the soma. The increased firing caused by axosomatic Kv7 channel block backpropagated into distal dendrites affecting their activity, despite these structures having fewer functional Kv7 channels. These results indicate that axonal Kv7 channels, by controlling axonal RMP and action potential threshold, are fundamental for regulating the inherent firing properties of CA1 hippocampal neurons.
| S-EPMC2408483 | biostudies-literature
Project description:Many years of studies have established that lipids can impact membrane protein structure and function through bulk membrane effects, by direct but transient annular interactions with the bilayer-exposed surface of protein transmembrane domains, and by specific binding to protein sites. Here, we focus on how phosphatidylinositol 4,5-bisphosphate (PIP2) and polyunsaturated fatty acids (PUFAs) impact ion channel function and how the structural details of the interactions of these lipids with ion channels are beginning to emerge. We focus on the Kv7 (KCNQ) subfamily of voltage-gated K+ channels, which are regulated by both PIP2 and PUFAs and play a variety of important roles in human health and disease. This article is part of a Special Issue entitled: Lipid order/lipid defects and lipid-control of protein activity edited by Dirk Schneider.
| S-EPMC5305565 | biostudies-literature
Project description:Aging is an independent risk factor for hypertension, cardiovascular morbidity, and mortality. However, detailed mechanisms linking aging to cardiovascular disease are unclear. We studied the aging effects on the role of perivascular adipose tissue and downstream vasoconstriction targets, voltage-dependent KV7 channels, and their pharmacological modulators (flupirtine, retigabine, QO58, and QO58-lysine) in a murine model. We assessed vascular function of young and old mesenteric arteries in vitro using wire myography and membrane potential measurements with sharp electrodes. We also performed bulk RNA sequencing and quantitative reverse transcription-polymerase chain reaction tests in mesenteric arteries and perivascular adipose tissue to elucidate molecular underpinnings of age-related phenotypes. Results revealed impaired perivascular adipose tissue-mediated control of vascular tone particularly via KV7.3-5 channels with increased age through metabolic and inflammatory processes and release of perivascular adipose tissue-derived relaxation factors. Moreover, QO58 was identified as novel pharmacological vasodilator to activate XE991-sensitive KCNQ channels in old mesenteric arteries. Our data suggest that targeting inflammation and metabolism in perivascular adipose tissue could represent novel approaches to restore vascular function during aging. Furthermore, KV7.3-5 channels represent a promising target in cardiovascular aging.
| S-EPMC8662361 | biostudies-literature
Project description:Within the vasculature Kv7 channels are key regulators of basal tone and contribute to a variety of receptor mediated vasorelaxants. The Kv7.4 isoform, abundant within the vasculature, is key to these processes and was recently shown to have an obligatory requirement of G-protein βγ subunits for its voltage dependent activity. There is an increasing appreciation that with 5 Gβ subunits and 12 Gγ subunits described in mammalian cells that different Gβ x γ x combinations can confer selectivity in Gβγ effector stimulation. Therefore, we aimed to characterize the Gβ subunit(s) which basally regulate Kv7.4 channels and native vascular Kv7 channels. In Chinese Hamster Ovary cells overexpressing Kv7.4 and different Gβx subunits only Gβ1, Gβ3, and Gβ5 enhanced Kv7.4 currents, increasing the activation kinetics and negatively shifting the voltage dependence of activation. In isolated rat renal artery myocytes, proximity ligation assay detected an interaction of Kv7.4 with Gβ1 and Gβ3 subunits, but not other isoforms. Morpholino directed knockdown of Gβ1 in rat renal arteries did not alter Kv7 dependent currents but reduced Kv7.4 protein expression. Knockdown of Gβ3 in rat renal arteries resulted in decreased basal K+ currents which were not sensitive to pharmacological inhibition of Kv7 channels. These studies implicate the Gβ1 subunit in the synthesis or stability of Kv7.4 proteins, whilst revealing that the Gβ3 isoform is responsible for the basal activity of Kv7 channels in native rat renal myocytes. These findings demonstrate that different Gβ subunits have important individual roles in ion channel regulation.
| S-EPMC6971187 | biostudies-literature