scholarly journals Polyunsaturated fatty acids produce a range of activators for heterogeneous IKs channel dysfunction

2019 ◽  
Vol 152 (2) ◽  
Author(s):  
Briana M. Bohannon ◽  
Xiaoan Wu ◽  
Xiongyu Wu ◽  
Marta E. Perez ◽  
Sara I. Liin ◽  
...  
Keyword(s):  
Ventricular Arrhythmias ◽  
Electrostatic Interactions ◽  
Voltage Dependence ◽  
Delayed Rectifier ◽  
Head Group ◽  
Maximal Conductance ◽  
Head Groups ◽  
K Current ◽  
Iks Channel ◽  
Congenital Long Qt Syndrome

Repolarization and termination of the ventricular cardiac action potential is highly dependent on the activation of the slow delayed-rectifier potassium IKs channel. Disruption of the IKs current leads to the most common form of congenital long QT syndrome (LQTS), a disease that predisposes patients to ventricular arrhythmias and sudden cardiac death. We previously demonstrated that polyunsaturated fatty acid (PUFA) analogues increase outward K+ current in wild type and LQTS-causing mutant IKs channels. Our group has also demonstrated the necessity of a negatively charged PUFA head group for potent activation of the IKs channel through electrostatic interactions with the voltage-sensing and pore domains. Here, we test whether the efficacy of the PUFAs can be tuned by the presence of different functional groups in the PUFA head, thereby altering the electrostatic interactions of the PUFA head group with the voltage sensor or the pore. We show that PUFA analogues with taurine and cysteic head groups produced the most potent activation of IKs channels, largely by shifting the voltage dependence of activation. In comparison, the effect on voltage dependence of PUFA analogues with glycine and aspartate head groups was half that of the taurine and cysteic head groups, whereas the effect on maximal conductance was similar. Increasing the number of potentially negatively charged moieties did not enhance the effects of the PUFA on the IKs channel. Our results show that one can tune the efficacy of PUFAs on IKs channels by altering the pKa of the PUFA head group. Different PUFAs with different efficacy on IKs channels could be developed into more personalized treatments for LQTS patients with a varying degree of IKs channel dysfunction.

scholarly journals A time- and voltage-dependent K+ current in single cardiac cells from bullfrog atrium.

1986 ◽  
Vol 88 (6) ◽  
pp. 777-798 ◽  
Author(s):  
J R Hume ◽  
W Giles ◽  
K Robinson ◽  
E F Shibata ◽  
R D Nathan ◽  
...  
Keyword(s):  
Time Course ◽  
Voltage Dependence ◽  
Outward Current ◽  
Cardiac Cells ◽  
Delayed Rectifier ◽  
Mechanical Dispersion ◽  
Atrial Cells ◽  
Voltage Dependent ◽  
K Current ◽  
Kinetics Of

Individual myocytes were isolated from bullfrog atrium by enzymatic and mechanical dispersion, and a one-microelectrode voltage clamp was used to record the slow outward K+ currents. In normal [K+]o (2.5 mM), the slow outward current tails reverse between -95 and -100 mV. This finding, and the observed 51-mV shift of Erev/10-fold change in [K+]o, strongly suggest that the "delayed rectifier" in bullfrog atrial cells is a K+ current. This current, IK, plays an important role in initiating repolarization, and it is distinct from the quasi-instantaneous, inwardly rectifying background current, IK. In atrial cells, IK does not exhibit inactivation, and very long depolarizing clamp steps (20 s) can be applied without producing extracellular K+ accumulation. The possibility of [K+]o accumulation contributing to these slow outward current changes was assessed by (a) comparing reversal potentials measured after short (2 s) and very long (15 s) activating prepulses, and (b) studying the kinetics of IK at various holding potentials and after systematically altering [K+]o. In the absence of [K+]o accumulation, the steady state activation curve (n infinity) and fully activated current-voltage (I-V) relation can be obtained directly. The threshold of the n infinity curve is near -50 mV, and it approaches a maximum at +20 mV; the half-activation point is approximately -16 mV. The fully activated I-V curve of IK is approximately linear in the range -40 to +30 mV. Semilog plots of the current tails show that each tail is a single-exponential function, which suggests that only one Hodgkin-Huxley conductance underlies this slow outward current. Quantitative analysis of the time course of onset of IK and of the corresponding envelope of tails demonstrate that the activation variable, n, must be raised to the second power to fit the sigmoid onset accurately. The voltage dependence of the kinetics of IK was studied by recording and curve-fitting activating and deactivating (tail) currents. The resulting 1/tau n curve is U-shaped and somewhat asymmetric; IK exhibits strong voltage dependence in the diastolic range of potentials. Changes in the [Ca2+]o in the superfusing Ringer's, and/or addition of La3+ to block the transmembrane Ca2+ current, show that the time course and magnitude of IK are not significantly modulated by transmembrane Ca2+ movements, i.e., by ICa. These experimentally measured voltage- and time-dependent descriptors of IK strongly suggest an important functional role for IK in atrial tissue: it initiates repolarization and can be an important determinant of rate-induced changes in action potential duration.

scholarly journals Different Head Group Dependence on The Lipid Thermodynamic Property of Myelin Basic Protein in the Lipid Monolayer

2021 ◽  
Author(s):  
Lei Zhang ◽  
Ming Zhang ◽  
Runguang Sun
Keyword(s):  
Myelin Basic Protein ◽  
Electrostatic Interactions ◽  
Basic Protein ◽  
Second Virial Coefficient ◽  
Virial Equation ◽  
Lipid Monolayer ◽  
Statistical Thermodynamic ◽  
Head Group ◽  
Myelin Lipid ◽  
Head Groups

Abstract The interaction between the role of 18.5 KDa myelin basic protein (MBP) isoform and phospholipids has been thought to maintain the stability and compactness of the myelin sheath structure. In this study, we describe the statistical thermodynamic theory of different concentrations’ effects on MBP in the major myelin lipid (1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (POPC), 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphoethanolamine (POPE)，and 1-palmitoyl-2-oleoyl-sn-glycero-3-phospho-L-serine (POPS)) monolayers at the air/subphase interface via Langmuir-Blodgett (LB) technique. A simple statistical mechanical theory is established that predicts the interaction between proteins and phosphate head groups at low surface pressures and the second virial coefficient dependences for the PC, PE, and PS head groups are illustrated. In addition, the surface pressure(π)-mean molecular area(mma) curves were also analyzed using two-dimensional virial equation of state (2D-VES). The positively charged showed that MBP may integrate into different lipid monolayers via hydrophobic and electrostatic interactions, which was found to be consistent with AFM observations of domain and aggregate structures as well as with changes in the surface morphology induced by MBP. These analyses pertaining to membrane structure will provide better insight into membrane modeling systems, especially the interaction between membrane molecules.

Ion channels based on bis-macrocyclic bolaamphiphiles: effects of hydrophobic substitutions

1998 ◽  
Vol 76 (7) ◽  
pp. 1015-1026 ◽  
Author(s):  
T M Fyles ◽  
D Loock ◽  
X Zhou
Keyword(s):  
Electrostatic Interactions ◽  
Voltage Dependence ◽  
Bilayer Membrane ◽  
Time Signal ◽  
Head Group ◽  
Signal Shape ◽  
Current Time ◽  
Cation Selectivity ◽  
Rapid Current ◽  
New Compounds

Four new bis-macrocyclic bolaamphiphiles were prepared to explore the effects of hydrophobic substitutions on ion transport. In bilayer vesicles the new compounds were remarkably similar to more hydrophilic derivatives prepared previously. Planar bilayer conductance experiments showed the new compounds induced an unique current-time signal consisting of a rapid rise time, followed by a slower decay time. Signal shape was cation dependent and was related to a modest selectivity between cations. Cation-anion selectivity was very high, approaching an ideal cation selectivity. One compound also showed voltage dependence of the signal shape and duration. Qualitative changes in signal shape, duration, and voltage dependence were provoked by variation in the electrolyte pH and by masking the head-group electrostatic interactions with low levels of barium ions. A model for the signal shape is proposed, involving a rapid current rise due to aggregate restructuring, followed by slower decay due to development of the local Donnan potential that results from the high cation-anion selectivity.Key words: ion channel, synthesis, bilayer membrane, bilayer clamp, mechanism.

Increasing I Ks corrects abnormal repolarization in rabbit models of acquired LQT2 and ventricular hypertrophy

2002 ◽  
Vol 283 (2) ◽  
pp. H664-H670 ◽  
Author(s):  
Xiaoping Xu ◽  
Joseph J. Salata ◽  
Jixin Wang ◽  
Ying Wu ◽  
Gan-Xin Yan ◽  
...  
Keyword(s):  
Ventricular Arrhythmias ◽  
Ventricular Hypertrophy ◽  
Voltage Dependence ◽  
Ventricular Myocytes ◽  
Delayed Rectifier ◽  
Long Qt ◽  
Early Afterdepolarizations ◽  
New Strategy ◽  
Rabbit Ventricular Myocytes ◽  
Qt Syndrome

Excessive action potential (AP) prolongation and early afterdepolarizations (EAD) are triggers of malignant ventricular arrhythmias. A slowly activating delayed rectifier K+ current ( I Ks) is important for repolarization of ventricular AP. We examined the effects of I Ks activation by a new benzodiazepine (L3) on the AP of control, dofetilide-treated, and hypertrophied rabbit ventricular myocytes. In both control and hypertrophied myocytes, L3 activated I Ks via a negative shift in the voltage dependence of activation and a slowing of deactivation. L3 had no effect on L-type Ca2+ current or other cardiac K+ currents tested. L3 shortened AP of control, dofetilide-treated, and hypertrophied myocytes more at 0.5 than 2 Hz. Selective activation of I Ks by L3 attenuates prolonged AP and eliminated EAD induced by rapidly activating delayed rectifier K+ current inhibition in control myocytes at 0.5 Hz and spontaneous EAD in hypertrophied myocytes at 0.2 Hz. Pharmacological activation of I Ks is a promising new strategy to suppress arrhythmias resulting from excessive AP prolongation in patients with certain forms of long QT syndrome or cardiac hypertrophy and failure.

Angiotensin II type 2 receptor-modulated changes in potassium currents in cultured neurons

1993 ◽  
Vol 265 (3) ◽  
pp. C607-C616 ◽  
Author(s):  
J. Kang ◽  
C. Sumners ◽  
P. Posner
Keyword(s):  
Angiotensin Ii ◽  
Ionic Current ◽  
Delayed Rectifier ◽  
Receptor Subtype ◽  
Cultured Neurons ◽  
Ang Ii ◽  
Maximal Conductance ◽  
K Current ◽  
At2 Receptors

We have previously shown that angiotensin II (ANG II) stimulates an increase in net outward ionic current (Ino) in neurons cocultured from neonate rat hypothalamus and brain stem, an effect mediated by ANG II type 2 (AT2) receptors. Ino consists mainly of K+ and Ca2+ currents, and in the present study we used whole cell voltage clamp procedures to define which of these currents are modulated by AT2 receptors. We determined that ANG II (50-100 nM) stimulated both transient K+ current (IA) and delayed-rectifier K+ current (IK) in cultured neurons. The effects were mediated by AT2 receptors (blocked by 1 microM PD-123177 but not by 1 microM losartan). For both IA and IK, ANG II elicited an increase in maximal conductance. By contrast, ANG II altered neither Ca(2+)-activated K+ current nor Ca2+ current. Our data demonstrate discrete AT2 receptor-mediated effects of ANG II on IA and IK in cultured neonate neurons. Importantly, these data provide an electrophysiological basis for behavioral or physiological effects (as yet undefined) mediated by this ANG II receptor subtype in the brain.

scholarly journals Voltage- and Ca(2+)-gated currents in zebrafish olfactory receptor neurons.

1996 ◽  
Vol 199 (5) ◽  
pp. 1115-1126 ◽  
Author(s):  
F S Corotto ◽  
D R Piper ◽  
N Chen ◽  
W C Michel
Keyword(s):  
Olfactory Receptor ◽  
Receptor Potential ◽  
Cell Voltage ◽  
Olfactory Receptor Neurons ◽  
Peak Amplitude ◽  
Delayed Rectifier ◽  
Maximal Conductance ◽  
Outward Currents ◽  
K Current ◽  
Receptor Neurons

Voltage- and Ca(2+)-gated currents were recorded from isolated olfactory receptor neurons (ORNs) of the zebrafish Danio rerio using the whole-cell voltage-clamp technique. Zebrafish ORNs had an average capacitance of 0.66 pF and an average apparent input resistance of 8.0 G omega. Depolarizing steps elicited transient inward currents followed by outward currents with transient and sustained components. The transient inward current (INa) was sensitive to 1 mumol l-1 tetrodotoxin, activated between -74mV and -64mV, and reached half-maximal conductance at -28 mV. Its peak amplitude averaged -101pA. Steady-state inactivation of INa was half-maximal at an average test potential of -78mV and recovery from inactivation proceeded with two time constants averaging 23 ms and 532 ms. A sustained, Co(2+)-sensitive current (ICa) activated between -44mV and -34mV and reached a peak amplitude averaging -9pA at -14mV. Outward currents were carried by K+, based on the reversal potentials of tail currents, and consisted of a Ca(2+)-dependent K+ current, a delayed rectifier current (IDR) and a transient K+ current (IA). The Ca(2+)-dependent K+ current (IK(Ca)) activated between -44mV and -34mV, whereas IDR and IA activated between -34mV and -24mV. In summary, zebrafish ORNs possess a complement of gated currents similar but not identical to that of ORNs from other vertebrates and which appears well suited for encoding a graded receptor potential into a train of action potentials.

Voltage-activated potassium currents of rabbit osteoclasts: effects of extracellular calcium

1994 ◽  
Vol 267 (4) ◽  
pp. C1103-C1111 ◽  
Author(s):  
L. G. Hammerland ◽  
A. S. Parihar ◽  
E. F. Nemeth ◽  
M. C. Sanguinetti
Keyword(s):  
Negative Charge ◽  
Voltage Dependence ◽  
Physiological Function ◽  
Inward Rectifier ◽  
Delayed Rectifier ◽  
Voltage Dependent ◽  
K Current ◽  
Kinetics Of ◽  
K Currents ◽  
Simple Surface

The effects of increased extracellular Ca2+ concentration ([Ca2+]e) were examined on a delayed-rectifier K+ current (IK) and an inward-rectifier K+ current (IK1) in rabbit osteoclasts. Elevation of [Ca2+]e from 1.8 to 18 mM shifted the half point for IK activation by +11.5 mV and the voltage dependence of inactivation by +9.7 mV and slowed the rate of IK activation and deactivation. These effects of elevated [Ca2+]e on IK are consistent with screening of cell surface negative charge. However, elevation of [Ca2+]e increased the voltage-dependent kinetics of IK inactivation at all potentials tested, inconsistent with that predicted by simple surface charge theory. This finding suggests an additional, regulatory role for [Ca2+]e in the gating of IK channels. Some osteoclasts had an IK1, which was decreased when [Ca2+]e was raised from 1.8 to 18 mM. The physiological function of both types of K+ currents remains to be determined, and it is not clear whether these currents are involved with the coupling of cytosolic [Ca2+] to [Ca2+]e.

Voltage-activated whole-cell K+ currents in lamina cells of the desert locust schistocerca gregaria

1999 ◽  
Vol 202 (14) ◽  
pp. 1939-1951 ◽  
Author(s):  
C. Benkenstein ◽  
M. Schmidt ◽  
M. Gewecke
Keyword(s):  
Voltage Dependence ◽  
Delayed Rectifier ◽  
Patch Clamp Technique ◽  
Whole Cell ◽  
Group I ◽  
Outward Currents ◽  
K Current ◽  
Group Ii ◽  
I Cells ◽  
In Cells

Voltage-dependent outward currents were studied in freshly dissociated somata of locust lamina cells. These currents were recorded in 142 somata using the whole-cell patch-clamp technique. By measuring the reversal potential at altered external [K+] and by replacing internal K+ with Cs+, we determined that the outward currents were carried by K+. The outward currents consist of a transient A-type K+ current (KA) and a delayed-rectifier-like K+ current (KD). Amongst the cells studied, we observed two distinct groups of cells. The most obvious difference between the two groups is that in group I cells the total outward current is dominated by KA (KA/KD=12.5), whereas in group II cells KA makes a smaller contribution (KA/KD=2.1). Furthermore, in cells of group I, the KA current shows a steeper voltage-dependence of activation, where VG50 is −29.9 mV and s is 11.9 (N=22), and inactivation, where VI50 is −84.5 mV and s is −6.3 (N=18), compared with the KA current in cells of group II: VG50=−7.9 mV; s=26.6 (N=36) and VI50=−68.4 mV; s=−7.5 (N=21) (VG50 is the voltage at which the whole-cell conductance G is half-maximally activated, VI50 is the voltage of half-maximal inactivation and s is the slope of the voltage-dependence). The transient KA current in group I cells decayed mono-exponentially. The decay of the KA current in group II cells was fitted with a double-exponential curve and was significantly faster than in group I cells. In contrast to the large differences in KA currents, the KD currents appeared to be quite similar in the two groups of cells.

scholarly journals Kv2.1 and silent Kv subunits underlie the delayed rectifier K+ current in cultured small mouse DRG neurons

2009 ◽  
Vol 296 (6) ◽  
pp. C1271-C1278 ◽  
Author(s):  
Elke Bocksteins ◽  
Adam L. Raes ◽  
Gerda Van de Vijver ◽  
Tine Bruyns ◽  
Pierre-Paul Van Bogaert ◽  
...  
Keyword(s):  
Sensory Neurons ◽  
Dorsal Root ◽  
Voltage Dependence ◽  
Physiological Role ◽  
Delayed Rectifier ◽  
Expression Systems ◽  
Drg Neurons ◽  
K Current ◽  
Heterologous Expression Systems ◽  
And Function

Silent voltage-gated K+ (Kv) subunits interact with Kv2 subunits and primarily modulate the voltage dependence of inactivation of these heterotetrameric channels. Both Kv2 and silent Kv subunits are expressed in the mammalian nervous system, but little is known about their expression and function in sensory neurons. This study reports the presence of Kv2.1, Kv2.2, and silent subunit Kv6.1, Kv8.1, Kv9.1, Kv9.2, and Kv9.3 mRNA in mouse dorsal root ganglia (DRG). Immunocytochemistry confirmed the protein expression of Kv2.x and Kv9.x subunits in cultured small DRG neurons. To investigate if Kv2 and silent Kv subunits are underlying the delayed rectifier K+ current ( IK) in these neurons, Kv2-mediated currents were isolated by the extracellular application of rStromatoxin-1 (ScTx) or by the intracellular application of Kv2 antibodies. Both ScTx- and anti-Kv2.1-sensitive currents displayed two components in their voltage dependence of inactivation. Together, both components accounted for approximately two-thirds of IK. A comparison with results obtained in heterologous expression systems suggests that one component reflects homotetrameric Kv2.1 channels, whereas the other component represents heterotetrameric Kv2.1/silent Kv channels. These observations support a physiological role for silent Kv subunits in small DRG neurons.

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