scholarly journals Interactions of polyamines with ion channels

1997 ◽  
Vol 325 (2) ◽  
pp. 289-297 ◽  
Author(s):  
Keith WILLIAMS
Keyword(s):  
Ion Channel ◽  
Glutamate Receptors ◽  
Inward Rectification ◽  
Resting Membrane Potential ◽  
Channel Pore ◽  
K Channels ◽  
Polyamine Analogues ◽  
Voltage Dependent ◽  
The Central Nervous System ◽  
And Control

Endogenous polyamines, in particular spermine, have been found to cause block and modulation of a number of types of ion channel. Intracellular spermine is responsible for intrinsic gating and rectification of strong inward rectifier K+ channels by directly plugging the ion channel pore. These K+ channels control the resting membrane potential in both excitable and non-excitable cells, and control the excitability threshold in neurons and muscle cells. Intracellular spermine causes inward rectification at some subtypes of Ca2+-permeable glutamate receptors in the central nervous system, again by plugging the receptor channel pore, and spermine can even permeate the ion channel of these receptors. Extracellular spermine has multiple effects at the N-methyl-D-aspartate (NMDA) subtype of glutamate receptor, including stimulation that increases the size of NMDA receptor currents, and voltage-dependent block. A number of polyamine-conjugated arthropod toxins and synthetic polyamine analogues are potent antagonists of glutamate receptors, and represent new tools with which to study these receptors. Interactions of polyamines with other types of cation channels have been reported. This area of research represents a new biology and a new pharmacology of polyamines.

scholarly journals Structural Similarities between Glutamate Receptor Channels and K+ Channels Examined by Scanning Mutagenesis

2001 ◽  
Vol 117 (4) ◽  
pp. 345-360 ◽  
Author(s):  
Victor A. Panchenko ◽  
Carla R. Glasser ◽  
Mark L. Mayer
Keyword(s):  
Dissociation Constant ◽  
Glutamate Receptors ◽  
Selectivity Filter ◽  
Periodic Pattern ◽  
K Channels ◽  
High Affinity ◽  
Aromatic Cage ◽  
Voltage Dependent ◽  
Complete Disruption ◽  
A Site

The pores of glutamate receptors and K+ channels share sequence homology, suggesting a conserved secondary structure. Scanning mutagenesis with substitution of alanine and tryptophan in GluR6 channels was performed based on the structure of KcsA. Our assay used disruption of voltage-dependent polyamine block to test for changes in the packing of pore-forming regions. Alanine scanning from D567 to R603 revealed reduced rectification resulting from channel block in two regions. A periodic pattern from F575 to M589 aligned with the pore helix in KcsA, whereas a cluster of sensitive positions around Q590, a site regulated by RNA editing, mapped to the selectivity filter in KcsA. Tryptophan scanning from D567 to R603 revealed similar patterns, but with a complete disruption of spermine block for 7 out of the 37 positions and a pM dissociation constant for Q590W. Molecular modeling with KcsA coordinates showed that GluR6 pore helix mutants disrupting polyamine block pack against M1 and M2, and are not exposed in the ion channel pore. In the selectivity filter, tryptophan creates an aromatic cage consistent with the pM dissociation constant for Q590W. A scan with glutamate substitution was used to map the cytoplasmic entrance to the pore based on charge neutralization experiments, which established that E594 was uniquely required for high affinity polyamine block. In E594Q mutants, introduction of glutamate at positions S593–L600 restored polyamine block at positions corresponding to surface-exposed residues in KcsA. Our results reinforce proposals that the pore region of glutamate receptors contains a helix and pore loop analogous to that found in K+ channels. At the cytoplasmic entrance of the channel, a negatively charged amino acid, located in an extended loop with solvent-exposed side chains, is required for high affinity polyamine block and probably attracts cations via a through space electrostatic mechanism.

scholarly journals Strong voltage-dependent inward rectification of inward rectifier K+ channels is caused by intracellular spermine

Cell ◽  
1995 ◽  
Vol 80 (1) ◽  
pp. 149-154 ◽  
Author(s):  
B Fakler ◽  
U Brändle ◽  
E Glowatzki ◽  
S Weidemann ◽  
H.-P Zenner ◽  
...  
Keyword(s):  
Inward Rectifier ◽  
Inward Rectification ◽  
K Channels ◽  
Voltage Dependent

Structural Correlates of K+ Channel Function

Physiology ◽  
1994 ◽  
Vol 9 (4) ◽  
pp. 169-173 ◽  
Author(s):  
M Taglialatela ◽  
AM Brown
Keyword(s):  
Ion Channel ◽  
Ionic Currents ◽  
The Other ◽  
K Channel ◽  
K Channels ◽  
Functional Studies ◽  
Channel Function ◽  
Voltage Dependent ◽  
K Currents

More complementary DNAs have been cloned for Voltage-dependent K+ channels than any other voltage-dependent ion channel. Purely functional studies anticipated this result because K+ currents are far more diverse than voltage-dependent Na+, Ca2+, or Cl currents, the other types of voltage-dependent ionic currents commonly dealt with.

scholarly journals Binding of κ-Conotoxin PVIIA to Shaker K+ Channels Reveals Different K+ and Rb+ Occupancies within the Ion Channel Pore

2004 ◽  
Vol 124 (1) ◽  
pp. 71-81 ◽  
Author(s):  
Anna Boccaccio ◽  
Franco Conti ◽  
Baldomero M. Olivera ◽  
Heinrich Terlau
Keyword(s):  
Ion Channel ◽  
Open Channel ◽  
K Channel ◽  
Closed Channel ◽  
Channel Pore ◽  
K Channels ◽  
Ion Channel Pore ◽  
Structural Work ◽  
High K ◽  
Insight Into

The x-ray structure of the KcsA channel at different [K+] and [Rb+] provided insight into how K+ channels might achieve high selectivity and high K+ transit rates and showed marked differences between the occupancies of the two ions within the ion channel pore. In this study, the binding of κ-conotoxin PVIIA (κ-PVIIA) to Shaker K+ channel in the presence of K+ and Rb+ was investigated. It is demonstrated that the complex results obtained were largely rationalized by differences in selectivity filter occupancy of this 6TM channels as predicted from the structural work on KcsA. κ-PVIIA inhibition of the Shaker K+ channel differs in the closed and open state. When K+ is the only permeant ion, increasing extracellular [K+] decreases κ-PVIIA affinity for closed channels by decreasing the “on” binding rate, but has no effect on the block of open channels, which is influenced only by the intracellular [K+]. In contrast, extracellular [Rb+] affects both closed- and open-channel binding. As extracellular [Rb+] increases, (a) binding to the closed channel is slightly destabilized and acquires faster kinetics, and (b) open channel block is also destabilized and the lowest block seems to occur when the pore is likely filled only by Rb+. These results suggest that the nature of the permeant ions determines both the occupancy and the location of the pore site from which they interact with κ-PVIIA binding. Thus, our results suggest that the permeant ion(s) within a channel pore can determine its functional and pharmacological properties.

Development of Inward Rectification and Control of Membrane Excitability in Mesencephalic V Neurons

2003 ◽  
Vol 89 (3) ◽  
pp. 1288-1298 ◽  
Author(s):  
Susumu Tanaka ◽  
Nanping Wu ◽  
Chie-Fang Hsaio ◽  
Jack Turman ◽  
Scott H. Chandler
Keyword(s):  
Cell Voltage ◽  
Resting Potential ◽  
Inward Rectification ◽  
Resting Membrane Potential ◽  
Membrane Excitability ◽  
Membrane Hyperpolarization ◽  
Whole Cell ◽  
Membrane Resonance ◽  
And Control ◽  
Zd 7288

The present study was performed to assess the postnatal development and functional roles of inward rectifying currents in rat mesencephalic trigeminal (Mes V) neurons, which are involved in the genesis and control of oral-motor activities. Whole cell voltage-clamp recordings obtained from Mes V neurons in brain stem slices identified fast ( I KIR) and slow ( I h) inward rectifying currents, which were specifically blocked by BaCl2 (300–500 μM) or 4-( N-ethyl- N-phenylamino)-1,2-dimethyl-6-(methylamino) pyrimidinium chloride (ZD 7288, 10 μM), respectively. The whole cell current density for these channels increased between postnatal days 2 to 12 (P2-P12), and the time courses for I h activation and deactivation were each well described by two time constants. Application of ZD 7288 produced membrane hyperpolarization in the majority of cells and prolonged afterhyperpolarization repolarization. Additionally, in the presence of ZD 7288, spike frequency was decreased and adaptation was more pronounced. Interestingly, these neurons exhibited a voltage-dependent membrane resonance (<10 Hz) that was prominent around resting potential and more negative to rest and was blocked by ZD 7288. These results suggest that I hcontributes to stabilizing resting membrane potential and controlling cell excitability. The presence of I himparts the neuron with the unique property of low-frequency membrane resonance; the ability to discriminate between synaptic inputs based on frequency content.

scholarly journals Ca2+-activated K+ Channels in Murine Endothelial Cells: Block by Intracellular Calcium and Magnesium

2008 ◽  
Vol 131 (2) ◽  
pp. 125-135 ◽  
Author(s):  
Jonathan Ledoux ◽  
Adrian D. Bonev ◽  
Mark T. Nelson
Keyword(s):  
Endothelial Cells ◽  
Membrane Potential ◽  
Intracellular Calcium ◽  
Membrane Current ◽  
Mesenteric Arteries ◽  
Equilibrium Potential ◽  
Inward Rectification ◽  
Resting Membrane Potential ◽  
Additional Increase ◽  
K Channels

The intermediate (IKCa) and small (SKCa) conductance Ca2+-sensitive K+ channels in endothelial cells (ECs) modulate vascular diameter through regulation of EC membrane potential. However, contribution of IKCa and SKCa channels to membrane current and potential in native endothelial cells remains unclear. In freshly isolated endothelial cells from mouse aorta dialyzed with 3 μM free [Ca2+]i and 1 mM free [Mg2+]i, membrane currents reversed at the potassium equilibrium potential and exhibited an inward rectification at positive membrane potentials. Blockers of large-conductance, Ca2+-sensitive potassium (BKCa) and strong inward rectifier potassium (Kir) channels did not affect the membrane current. However, blockers of IKCa channels, charybdotoxin (ChTX), and of SKCa channels, apamin (Ap), significantly reduced the whole-cell current. Although IKCa and SKCa channels are intrinsically voltage independent, ChTX- and Ap-sensitive currents decreased steeply with membrane potential depolarization. Removal of intracellular Mg2+ significantly increased these currents. Moreover, concomitant reduction of the [Ca2+]i to 1 μM caused an additional increase in ChTX- and Ap-sensitive currents so that the currents exhibited theoretical outward rectification. Block of IKCa and SKCa channels caused a significant endothelial membrane potential depolarization (≈11 mV) and decrease in [Ca2+]i in mesenteric arteries in the absence of an agonist. These results indicate that [Ca2+]i can both activate and block IKCa and SKCa channels in endothelial cells, and that these channels regulate the resting membrane potential and intracellular calcium in native endothelium.

Voltage dependence of excitatory postsynaptic potentials of rat neocortical neurons

1991 ◽  
Vol 65 (2) ◽  
pp. 371-382 ◽  
Author(s):  
R. A. Deisz ◽  
G. Fortin ◽  
W. Zieglgansberger
Keyword(s):  
Action Potentials ◽  
Inward Rectification ◽  
Resting Membrane Potential ◽  
Excitatory Postsynaptic Potentials ◽  
Postsynaptic Potentials ◽  
Electrode Current ◽  
Time Integral ◽  
Neocortical Neurons ◽  
Voltage Dependent

1. The properties of excitatory postsynaptic potentials (EPSPs) of rat neocortical neurons were investigated with a fast single-electrode current-voltage clamp in vitro. Typically, apparently pure EPSPs were obtained by selection of electric stimuli of low intensity. 2. The amplitude and time integral of the EPSP increased when the neuron was depolarized. At threshold for generation of action potentials, the amplitude of EPSPs was increased by approximately 30% [from 5.0 +/- 2.1 to 6.3 +/- 1.0 (SD) mV, n = 12]. The integral of EPSPs was maximally about fourfold (3.7 +/- 1.5, n = 16) larger than at resting membrane potential (Em). The mechanisms involved in this augmentation of EPSPs were further investigated. 3. The amplitude and the time integral of excitatory postsynaptic currents (EPSCs) decreased linearly with shifts in command potential from -100 to -60 mV. The decrease of the EPSC integral with depolarization indicates that the enhancement of the EPSP may be brought about by recruitment of a voltage-dependent inward current. 4. Evoking EPSPs at various delays after the onset of small depolarizing current pulses (0.3-0.6 nA, 600 ms) revealed that augmentation decays with time. The integral of EPSPs evoked approximately 80 ms after the onset of the current pulse was 3.7 (+/- 1.5, n = 16) times larger than at Em. The integral of EPSPs evoked at 480 ms. however, were only twofold (+/- 0.7, n = 16) larger. Hence EPSPs evoked after a delay of 80 ms were 1.7-fold (+/- 0.4, n = 24) larger than EPSPs evoked after 480 ms. EPSCs were independent of the delay of stimulation at all potentials. 5. Intracellular application of the lidocaine derivative N-(2,6-dimethyl-phenylcarbamoylmethyl) triethylammonium bromide (QX 314) at 100 mM from pipettes rapidly abolished fast action potentials and inward rectification. During comparable depolarizations the increase in EPSP integrals was much smaller in QX 314-treated neurons than in controls. On average, the integral of EPSPs evoked at 70-90 ms was 1.7 times (+/- 1.0) larger than at Em, and the integral of EPSPs evoked with larger delays was close to the value obtained at resting Em (0.9 +/- 0.3, n = 8). The ratio of EPSP integrals early versus late (1.8 +/- 0.5) is comparable to controls, suggesting that QX 314-sensitive currents are unlikely to be involved in the time-dependent enhancement. 6. Mimicking EPSPs by brief depolarizations atop long depolarizations revealed a time- and voltage-dependent enhancement comparable to that of EPSPs.(ABSTRACT TRUNCATED AT 400 WORDS)

scholarly journals Novel Gating Mechanism of Polyamine Block in the Strong Inward Rectifier K Channel Kir2.1

1999 ◽  
Vol 113 (4) ◽  
pp. 555-564 ◽  
Author(s):  
Jong-Kook Lee ◽  
Scott A. John ◽  
James N. Weiss
Keyword(s):  
Open Channel ◽  
Cell Types ◽  
Inward Rectification ◽  
K Channel ◽  
Resting Membrane Potential ◽  
Channel Block ◽  
Open Channel Block ◽  
Gating Mechanism ◽  
Voltage Dependent ◽  
Polyamine Toxins

Inward rectifying K channels are essential for maintaining resting membrane potential and regulating excitability in many cell types. Previous studies have attributed the rectification properties of strong inward rectifiers such as Kir2.1 to voltage-dependent binding of intracellular polyamines or Mg to the pore (direct open channel block), thereby preventing outward passage of K ions. We have studied interactions between polyamines and the polyamine toxins philanthotoxin and argiotoxin on inward rectification in Kir2.1. We present evidence that high affinity polyamine block is not consistent with direct open channel block, but instead involves polyamines binding to another region of the channel (intrinsic gate) to form a blocking complex that occludes the pore. This interaction defines a novel mechanism of ion channel closure.

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