PIP2 regulation of KCNQ channels: biophysical and molecular mechanisms for lipid modulation of voltage-dependent gating

Objective: This review sought to bring evidence of studies addressing the mechanisms of action of topiramate in the prevention and treatment of migraine. Background: Migraine is a neurovascular disorder that affects a large part of the world population. The use of prophylactics contributes to the decrease in the frequency and severity of this disease. Among the antiepileptic drugs, the topiramate, has proven to be the most effective for the treatment of migraine. Although the mechanism of action of this drug is still not well elucidated in the literature, there are several molecular mechanisms proposed. Methodology: A survey was carried out in the literature, from February to March 2018, in different databases, using the descriptors: topiramate, migraine and mechanisms of action. After a careful selection, 25 manuscripts were chosen for this review. Results: Evidence from a number of studies has indicated that the main mechanisms of action of topiramate are related to the modulation of voltage-dependent sodium and calcium ion channels, blockade of excitatory glutamate transmission and inhibition by gamma-aminobutyric acid receptors (GABA), AMPA/kainate and some isoenzymes of carbonic anhydrase. In addition, topiramate is involved in the suppression of cortical spreading depression, besides influencing trigeminovascular activity, and neuronal excitability. Conclusion: Thus, topiramate could be involved in the prevention of major events of the pathophysiology of migraine. Acting directly on cortical spreading depression (DAC), trigeminovascular signals and decreased central sensitization of migraine pain.

Download Full-text

Molecular mechanisms of regulation of fast-inactivating voltage-dependent transient outward K+current in mouse heart by cell volume changes

The Journal of Physiology ◽

10.1113/jphysiol.2005.091264 ◽

2005 ◽

Vol 568 (2) ◽

pp. 423-443 ◽

Cited By ~ 16

Author(s):

Guan-Lei Wang ◽

Ge-Xin Wang ◽

Shintaro Yamamoto ◽

Linda Ye ◽

Heather Baxter ◽

...

Keyword(s):

Cell Volume ◽

Molecular Mechanisms ◽

Mouse Heart ◽

Volume Changes ◽

Voltage Dependent ◽

K Current

Download Full-text

Ca2+-independent but voltage-dependent quantal catecholamine secretion (CiVDS) in the mammalian sympathetic nervous system

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1902444116 ◽

2019 ◽

Vol 116 (40) ◽

pp. 20201-20209 ◽

Cited By ~ 4

Author(s):

Rong Huang ◽

Yuan Wang ◽

Jie Li ◽

Xiaohan Jiang ◽

Yinglin Li ◽

...

Keyword(s):

Nervous System ◽

Sympathetic Nervous System ◽

Molecular Mechanisms ◽

Catecholamine Release ◽

Sensory Cells ◽

Voltage Dependent ◽

Sympathetic Nervous ◽

Vesicular Exocytosis ◽

Adrenal Chromaffin ◽

Ganglion Neurons

Action potential-induced vesicular exocytosis is considered exclusively Ca2+ dependent in Katz’s Ca2+ hypothesis on synaptic transmission. This long-standing concept gets an exception following the discovery of Ca2+-independent but voltage-dependent secretion (CiVDS) and its molecular mechanisms in dorsal root ganglion sensory neurons. However, whether CiVDS presents only in sensory cells remains elusive. Here, by combining multiple independent recordings, we report that [1] CiVDS robustly presents in the sympathetic nervous system, including sympathetic superior cervical ganglion neurons and slice adrenal chromaffin cells, [2] uses voltage sensors of Ca2+ channels (N-type and novel L-type), and [3] contributes to catecholamine release in both homeostatic and fight-or-flight like states; [4] CiVDS-mediated catecholamine release is faster than that of Ca2+-dependent secretion at the quantal level and [5] increases Ca2+ currents and contractility of cardiac myocytes. Together, CiVDS presents in the sympathetic nervous system with potential physiological functions, including cardiac muscle contractility.

Download Full-text

Molecular Mechanisms of Mechanoreceptor Adaptation

Physiology ◽

10.1152/physiologyonline.1994.9.2.53 ◽

1994 ◽

Vol 9 (2) ◽

pp. 53-59

Author(s):

OP Hamill ◽

DW, McBride

Keyword(s):

Hair Cell ◽

Hair Cells ◽

Molecular Mechanisms ◽

Mechanosensitive Channel ◽

Cell Adaptation ◽

Stimulus Domain ◽

Dynamic Sensitivity ◽

Voltage Dependent ◽

Channel Currents

Mechanoreceptor adaptation to maintained stimulation serves to maximize dynamic sensitivity over a broad stimulus domain. Mechanosensitive channel currents in hair cells and oocytes show similar voltage-dependent adaptation. However, in the hair cell, adaptation appears dependent on Ca2+ influx, whereas in the oocyte, it is intrinsically voltage sensitive.

Download Full-text

Conformational changes in a pore-forming region underlie voltage-dependent “loop gating” of an unapposed connexin hemichannel

The Journal of General Physiology ◽

10.1085/jgp.200910207 ◽

2009 ◽

Vol 133 (6) ◽

pp. 555-570 ◽

Cited By ~ 52

Author(s):

Qingxiu Tang ◽

Terry L. Dowd ◽

Vytas K. Verselis ◽

Thaddeus A. Bargiello

Keyword(s):

Conformational Changes ◽

Disulfide Bonds ◽

Molecular Mechanisms ◽

Extracellular Loop ◽

Connexin Gene ◽

Gating Mechanism ◽

Biochemical Assays ◽

Voltage Dependent ◽

Tm Domain ◽

Connexin Hemichannel

The structure of the pore is critical to understanding the molecular mechanisms underlying selective permeation and voltage-dependent gating of channels formed by the connexin gene family. Here, we describe a portion of the pore structure of unapposed hemichannels formed by a Cx32 chimera, Cx32*Cx43E1, in which the first extracellular loop (E1) of Cx32 is replaced with the E1 of Cx43. Cysteine substitutions of two residues, V38 and G45, located in the vicinity of the border of the first transmembrane (TM) domain (TM1) and E1 are shown to react with the thiol modification reagent, MTSEA–biotin-X, when the channel resides in the open state. Cysteine substitutions of flanking residues A40 and A43 do not react with MTSEA–biotin-X when the channel resides in the open state, but they react with dibromobimane when the unapposed hemichannels are closed by the voltage-dependent “loop-gating” mechanism. Cysteine substitutions of residues V37 and A39 do not appear to be modified in either state. Furthermore, we demonstrate that A43C channels form a high affinity Cd2+ site that locks the channel in the loop-gated closed state. Biochemical assays demonstrate that A43C can also form disulfide bonds when oocytes are cultured under conditions that favor channel closure. A40C channels are also sensitive to micromolar Cd2+ concentrations when closed by loop gating, but with substantially lower affinity than A43C. We propose that the voltage-dependent loop-gating mechanism for Cx32*Cx43E1 unapposed hemichannels involves a conformational change in the TM1/E1 region that involves a rotation of TM1 and an inward tilt of either each of the six connexin subunits or TM1 domains.

Download Full-text

Function and Plasticity of Electrical Synapses in the Mammalian Brain: Role of Non-Junctional Mechanisms

10.20944/preprints202112.0384.v1 ◽

2021 ◽

Author(s):

Sebastian Curti ◽

Federico Davoine ◽

Antonella Dapino

Keyword(s):

Molecular Mechanisms ◽

Mammalian Brain ◽

Synaptic Membrane ◽

Electrical Transmission ◽

Electrical Synapses ◽

Electrophysiological Properties ◽

Voltage Dependent ◽

Theoretical Evidence ◽

Circuit Function

Electrical transmission between neurons is largely mediated by gap junctions. These junctions allow the direct flow of electric current between neurons, and in mammals are mostly composed of the protein connexin (Cx)36. Circuits of electrically coupled neurons are widespread in these animals, plus, experimental and theoretical evidence supports the notion that, beyond synchronicity, these circuits are able to perform sophisticated operations like lateral excitation and inhibition, noise reduction, as well as the ability to selectively respond upon coincident excitatory inputs. Although once considered stereotyped and unmodifiable, we now know that electrical synapses are subject to modulation and, by reconfiguring neural circuits, these modulations can alter relevant operations. The strength of electrical synapses depends on gap junction conductance, as well as on its functional interaction with the electrophysiological properties of coupled neurons. In particular, voltage dependent channels of the non-synaptic membrane critically determine the efficacy of transmission at these contacts. Consistently, modulatory actions on these channels have been shown to represent relevant mechanisms of plasticity of electrical synaptic transmission. Here we review recent evidence on the regulation of electrical synapses of mammals, the underlying molecular mechanisms, and the possible ways in which they affect circuit function.

Download Full-text

A PIP2 substitute mediates voltage sensor-pore coupling in KCNQ activation

Communications Biology ◽

10.1038/s42003-020-1104-0 ◽

2020 ◽

Vol 3 (1) ◽

Cited By ~ 2

Author(s):

Yongfeng Liu ◽

Xianjin Xu ◽

Junyuan Gao ◽

Moawiah M. Naffaa ◽

Hongwu Liang ◽

...

Keyword(s):

Ventricular Myocytes ◽

Membrane Lipids ◽

Voltage Sensor ◽

Structural Basis ◽

Drug Induced ◽

Kcnq Channels ◽

Voltage Dependent ◽

Pore Opening ◽

Action Potential Prolongation ◽

Voltage Sensor Domain

AbstractKCNQ family K+ channels (KCNQ1-5) in the heart, nerve, epithelium and ear require phosphatidylinositol 4,5-bisphosphate (PIP2) for voltage dependent activation. While membrane lipids are known to regulate voltage sensor domain (VSD) activation and pore opening in voltage dependent gating, PIP2 was found to interact with KCNQ1 and mediate VSD-pore coupling. Here, we show that a compound CP1, identified in silico based on the structures of both KCNQ1 and PIP2, can substitute for PIP2 to mediate VSD-pore coupling. Both PIP2 and CP1 interact with residues amongst a cluster of amino acids critical for VSD-pore coupling. CP1 alters KCNQ channel function due to different interactions with KCNQ compared with PIP2. We also found that CP1 returned drug-induced action potential prolongation in ventricular myocytes to normal durations. These results reveal the structural basis of PIP2 regulation of KCNQ channels and indicate a potential approach for the development of anti-arrhythmic therapy.

Download Full-text

Amino acid substitutions in the FXYD motif enhance phospholemman-induced modulation of cardiac L-type calcium channels

AJP Cell Physiology ◽

10.1152/ajpcell.00149.2010 ◽

2010 ◽

Vol 299 (5) ◽

pp. C1203-C1211 ◽

Cited By ~ 10

Author(s):

Kai Guo ◽

Xianming Wang ◽

Guofeng Gao ◽

Congxin Huang ◽

Keith S. Elmslie ◽

...

Keyword(s):

Amino Acid ◽

Calcium Channels ◽

Molecular Mechanisms ◽

Channel Gating ◽

Fine Tuning ◽

Amino Acid Substitutions ◽

Dependent Inactivation ◽

Voltage Dependent ◽

Kinetics Of

We have found that phospholemman (PLM) associates with and modulates the gating of cardiac L-type calcium channels (Wang et al., Biophys J 98: 1149–1159, 2010). The short 17 amino acid extracellular NH2-terminal domain of PLM contains a highly conserved PFTYD sequence that defines it as a member of the FXYD family of ion transport regulators. Although we have learned a great deal about PLM-dependent changes in calcium channel gating, little is known regarding the molecular mechanisms underlying the observed changes. Therefore, we investigated the role of the PFTYD segment in the modulation of cardiac calcium channels by individually replacing Pro-8, Phe-9, Thr-10, Tyr-11, and Asp-12 with alanine (P8A, F9A, T10A, Y11A, D12A). In addition, Asp-12 was changed to lysine (D12K) and cysteine (D12C). As expected, wild-type PLM significantly slows channel activation and deactivation and enhances voltage-dependent inactivation (VDI). We were surprised to find that amino acid substitutions at Thr-10 and Asp-12 significantly enhanced the ability of PLM to modulate CaV1.2 gating. T10A exhibited a twofold enhancement of PLM-induced slowing of activation, whereas D12K and D12C dramatically enhanced PLM-induced increase of VDI. The PLM-induced slowing of channel closing was abrogated by D12A and D12C, whereas D12K and T10A failed to impact this effect. These studies demonstrate that the PFXYD motif is not necessary for the association of PLM with CaV1.2. Instead, since altering the chemical and/or physical properties of the PFXYD segment alters the relative magnitudes of opposing PLM-induced effects on CaV1.2 channel gating, PLM appears to play an important role in fine tuning the gating kinetics of cardiac calcium channels and likely plays an important role in shaping the cardiac action potential and regulating Ca2+ dynamics in the heart.

Download Full-text

p63 supports aerobic respiration through hexokinase II

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1508871112 ◽

2015 ◽

Vol 112 (37) ◽

pp. 11577-11582 ◽

Cited By ~ 42

Author(s):

Guiditta Viticchiè ◽

Massimiliano Agostini ◽

Anna Maria Lena ◽

Mara Mancini ◽

Huiqing Zhou ◽

...

Keyword(s):

Molecular Mechanisms ◽

Direct Interaction ◽

Human Keratinocytes ◽

Basal Respiration ◽

Glycolytic Enzyme ◽

Metabolic Reprogramming ◽

Hexokinase Ii ◽

Chip Sequencing ◽

Voltage Dependent ◽

Responsive Element

Short p63 isoform, ΔNp63, is crucial for epidermis formation, and it plays a pivotal role in controlling the turnover of basal keratinocytes by regulating the expression of a subset of genes involved in cell cycle and cell adhesion programs. The glycolytic enzyme hexokinase 2 (HK2) represents the first step of glucose utilization in cells. The family of HKs has four isoforms that differ mainly in their tissue and subcellular distribution. The preferential mitochondrial localization of HK2 at voltage-dependent anion channels provides access to ATP generated by oxidative phosphorylation and generates an ADP/ATP recycling mechanism to maintain high respiration rates and low electron leak. Here, we report that ΔNp63 depletion in human keratinocytes impairs mitochondrial basal respiration and increases mitochondrial membrane polarization and intracellular reactive oxygen species. We show ΔNp63-dependent regulation of HK2 expression, and we use ChIP, validated by p63-Chip sequencing genomewide profiling analysis, and luciferase assays to demonstrate the presence of one p63-specific responsive element within the 15th intronic region of the HK2 gene, providing evidence of a direct interaction. Our data support the notion of ΔNp63 as a master regulator in epithelial cells of a combined subset of molecular mechanisms, including cellular energy metabolism and respiration. The ΔNp63–HK2 axis is also present in epithelial cancer cells, suggesting that ΔNp63 could participate in cancer metabolic reprogramming.

Download Full-text

The syndromic deafness mutation G12R impairs fast and slow gating in Cx26 hemichannels

The Journal of General Physiology ◽

10.1085/jgp.201711782 ◽

2018 ◽

Vol 150 (5) ◽

pp. 697-711 ◽

Cited By ~ 9

Author(s):

Isaac E. García ◽

Felipe Villanelo ◽

Gustavo F. Contreras ◽

Amaury Pupo ◽

Bernardo I. Pinto ◽

...

Keyword(s):

Molecular Mechanisms ◽

Intracellular Loop ◽

Open Probability ◽

Gain Of Function ◽

Gating Mechanism ◽

N Terminus ◽

Voltage Dependent ◽

Fast Gating ◽

Dynamics Simulations ◽

Connexin Hemichannels

Mutations in connexin 26 (Cx26) hemichannels can lead to syndromic deafness that affects the cochlea and skin. These mutations lead to gain-of-function hemichannel phenotypes by unknown molecular mechanisms. In this study, we investigate the biophysical properties of the syndromic mutant Cx26G12R (G12R). Unlike wild-type Cx26, G12R macroscopic hemichannel currents do not saturate upon depolarization, and deactivation is faster during hyperpolarization, suggesting that these channels have impaired fast and slow gating. Single G12R hemichannels show a large increase in open probability, and transitions to the subconductance state are rare and short-lived, demonstrating an inoperative fast gating mechanism. Molecular dynamics simulations indicate that G12R causes a displacement of the N terminus toward the cytoplasm, favoring an interaction between R12 in the N terminus and R99 in the intracellular loop. Disruption of this interaction recovers the fast and slow voltage-dependent gating mechanisms. These results suggest that the mechanisms of fast and slow gating in connexin hemichannels are coupled and provide a molecular mechanism for the gain-of-function phenotype displayed by the syndromic G12R mutation.

Download Full-text