Conformational model for ion permeation in membrane channels: a comparison with multi-ion models and applications to calcium channel permeability

Mironov, S.L.

doi:10.1016/s0006-3495(92)81628-4

Cited by 19 publications

(20 citation statements)

References 49 publications

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“…The I–V relationship of the L‐type Ca 2+ channel currents demonstrated non‐ohmic behaviour, resembling that measured for whole‐cell currents in heart cells (McDonald et al 1986). This relationship is also consistent with theoretical predictions of Ca 2+ channel permeability (Mironov, 1992). The null potential ( E null ) corresponded to a command voltage of +120 mV.…”

Section: Resultssupporting

confidence: 91%

L‐type Ca²⁺ channels in inspiratory neurones of mice and their modulation by hypoxia

Mironov

Richter

1998

The Journal of Physiology

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Whole‐cell (ICa) and single Ca2+ channel currents were measured in inspiratory neurones of neonatal mice (4–12 days old). During whole‐cell recordings, ICa slowly declined and disappeared within 10–20 min. The run‐down was delayed during hypoxia, indicating ICa potentiation. Ca2+ channels were recorded in cell‐attached patches using pipettes which contained 110 mm Ba2+. L‐type Ca2+ channels exhibited a non‐ohmic I–V relationship. The slope conductance was 24 pS below and 50 pS above their null potential. The open probability of the channels increased during oxygen depletion, reaching a maximum 2 min after the onset of hypoxia. Restoration of the oxygen supply brought the channel activity back to initial levels. The channel activity was enhanced by 3–30 μmS(–)Bay K 8644, an agonist of L‐type Ca2+ channels. The open probability was increased about 3‐fold and the activation curve was shifted by 20 mV in the hyperpolarizing direction. In the presence of the agonist, channel open time increased and long openings appeared. Agonist‐modulated channels were also potentiated during oxygen depletion. The effect was due to an increase in open time and a decrease in closed time. The channels were inhibited by bath application of nifedipine (10 μm) and nitrendipine (20 μm). Weak bases such as NH4Cl and TMA increased and weak acids such as sodium acetate and propionate decreased activity of the channels, indicating that they are modulated by intracellular pH. Bath application of 1 μm forskolin enhanced the channel activity, whereas 500 μm NaF suppressed it. L‐type Ca2+ channels were modulated by an agonist for mGluR1/5 receptors, (S)‐3,5‐dihydrophenylglycine (DHPG, 5 μm). In its presence, the hypoxic facilitation of channels was abolished. After blockade of L‐type Ca2+ channels, the respiratory response to hypoxia was modified. The transient enhancement of the respiratory rhythm (augmentation) was no longer evident and the secondary depression occurred earlier. We suggest that L‐type Ca2+ channels contribute to the early hypoxic response of the respiratory centre. Glutamate release during hypoxia stimulates postsynaptic metabotropic glutamate receptors, which activate the Ca2+ channels.

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Section: Resultssupporting

confidence: 91%

L‐type Ca²⁺ channels in inspiratory neurones of mice and their modulation by hypoxia

Mironov

Richter

1998

The Journal of Physiology

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“…This theory is still taught in textbooks (2) and similar theories are still used to model ion transport (3). Ion channel experiments are also routinely interpreted in terms of this model (4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15). However, the assumption that both the energy barriers/wells and the ions themselves are unaffected by the electrostatic potential of nearby ions contradicts the findings of recent ion channel simulations, both on the atomistic timescale (16,17) and at steady state (18).…”

Section: Introductionmentioning

confidence: 99%

Synthetic Nanopores as a Test Case for Ion Channel Theories: The Anomalous Mole Fraction Effect without Single Filing

Gillespie

Boda

et al. 2008

Biophysical Journal

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The predictions of a theory for the anomalous mole fraction effect (AMFE) are tested experimentally with synthetic nanopores in plastic. The negatively charged synthetic nanopores under consideration are highly cation selective and 50 A in diameter at their smallest point. These pores exhibit an AMFE in mixtures of Ca(2+) and monovalent cations. An AMFE occurs when the conductance through a pore is lower in a mixture of salts than in the pure salts at the same concentration. For ion channels, the textbook interpretation of the AMFE is that multiple ions move through the pore in coordinated, single-file motion. However, because the synthetic nanopores are so wide, their AMFE shows that single filing is not necessary for the AMFE. It is shown that the AMFE in the synthetic nanopores is explained by a theory of preferential ion selectivity. The unique properties of the synthetic nanopores allow us to experimentally confirm several predictions of this theory. These same properties make synthetic nanopores an interesting new platform to test theories of ion channel permeation and selectivity in general.

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“…Ca 2+ ions possess, in fact, the paradoxical ability to block Na + currents through Ca 2+ channels at micromolar Ca 2+ concentrations and to permeate the channel when Ca 2+ is raised to millimolar concentrations. The issue is then to prove whether this occurs: (1) by strong interactions between ions occupying two distinct sites of high‐affinity for Ca 2+ inside the channel (Aimers & McCleskey, 1984; Hess & Tsien, 1984; Lansman, Hess & Tsien, 1986), (2) by assuming specific ion‐channel interactions at a single locus inside the pore, which favours Ca 2+ block and permeation by repeated Ca 2+ occupancies (Lux et al 1990; Mironov, 1992), or (3) by a ‘knock‐on’ mechanism at a single site for Ca 2+ in which ion conduction and block occur by replacements of bound ions (ion exchange) rather than by pure ion‐ion interactions (Armstrong & Neyton, 1992).…”

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confidence: 99%

Ca²⁺ and Na⁺ permeability of high‐threshold Ca²⁺ channels and their volt age‐dependent block by Mg²⁺ ions in chick sensory neurones

Carbone

Lux

Carabelli

et al. 1997

The Journal of Physiology

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1. The Mg¥ block of Na¤ and Ca¥ currents through high-voltage activated (HVA; L_ and N_type) Ca¥ channels was studied in chick dorsal root ganglion neurones. 2. In low extracellular [Ca¥] (< 10¦Ì Ò) and with Naº and Cs¸as the main charge carriers (120 mÒ), HVA Na¤ currents started to activate at −40 mV, reached inward peak values near 0 mV and reversed at about +40 mV. 3. Addition of 30-500 ìÒ Mg¥ to the bath caused a strong depression of inward Na¤ currents that was voltage and dose dependent (KD = 39 ìÒ in 120 mÒ Na¤ at −10 mV). The block was maximal at negative potentials (< −70 mV) and decreased with increasing positive potentials, suggesting that Mg¥ cannot escape to the cell interior. 4. Block of Ca¥ currents by Mg¥ was also voltage dependent, but by three orders of magnitude less potent than with Na¤ currents (KD = 24 mÒ in 2 mÒ Ca¥ at −30 mV). The high concentration of Mg¥ caused a prominent voltage shift of channel gating kinetics induced by surface charge screening effects. To compensate for this, Mg¥ block of inward Ca¥ currents was estimated from the instantaneous I-V relationships on return from very positive potentials (+100 mV). 5. Inward Na¤ and Ca¥ tail currents following depolarization to +90 mV were markedly depressed, suggesting that channels cleared of Mg¥ ions during strong depolarization are quickly re-blocked on return to negative potentials. The kinetics of re-block by Mg¥ was too fast (< 100 ìs) to be resolved by our recording apparatus. This implies a rate of entry for Mg¥ > 1·45 ² 10Ì Ò¢ s¢ when Na¤ is the permeating ion and a rate approximately 3 orders of magnitude smaller for Ca¥. 6. Mg¥ unblock of HVA Na¤ currents at +100 mV was independent of the size of outward currents, whether Na¤, Cs¤ or NMG¤ were the main internal cations. 7. Consistent with the idea of a high-affinity binding site for Ca¥ inside the channel, micromolar amounts of Ca¥ caused a strong depression of Na¤ currents between −40 and 0 mV, which was effectively relieved with more positive as well as with negative potentials (KD = 0·7 ìÒ in 120 mÒ Na¤ at −20 mV). In this case, the kinetics of re-block could be resolved and gave rates of entry and exit for Ca¥ of 1·4 ² 10Ì Ò¢ s¢ and 2·95 ² 10Â s¢, respectively. 8. The strong voltage dependence and weak current dependence of HVA channel block by divalent cations and the markedly different KD values of Na¤ and Ca¥ current block by Mg¥ can be well described by a previously proposed model for Ca¥ channel permeation based on interactions between the permeating ion and the negative charges forming the high-affinity binding site for Ca¥ inside the pore (Lux, Carbone & Zucker, 1990).

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Conformational model for ion permeation in membrane channels: a comparison with multi-ion models and applications to calcium channel permeability

Cited by 19 publications

References 49 publications

L‐type Ca²⁺ channels in inspiratory neurones of mice and their modulation by hypoxia

L‐type Ca²⁺ channels in inspiratory neurones of mice and their modulation by hypoxia

Synthetic Nanopores as a Test Case for Ion Channel Theories: The Anomalous Mole Fraction Effect without Single Filing

Ca²⁺ and Na⁺ permeability of high‐threshold Ca²⁺ channels and their volt age‐dependent block by Mg²⁺ ions in chick sensory neurones

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Conformational model for ion permeation in membrane channels: a comparison with multi-ion models and applications to calcium channel permeability

Cited by 19 publications

References 49 publications

L‐type Ca2+ channels in inspiratory neurones of mice and their modulation by hypoxia

L‐type Ca2+ channels in inspiratory neurones of mice and their modulation by hypoxia

Synthetic Nanopores as a Test Case for Ion Channel Theories: The Anomalous Mole Fraction Effect without Single Filing

Ca2+ and Na+ permeability of high‐threshold Ca2+ channels and their volt age‐dependent block by Mg2+ ions in chick sensory neurones

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L‐type Ca²⁺ channels in inspiratory neurones of mice and their modulation by hypoxia

L‐type Ca²⁺ channels in inspiratory neurones of mice and their modulation by hypoxia

Ca²⁺ and Na⁺ permeability of high‐threshold Ca²⁺ channels and their volt age‐dependent block by Mg²⁺ ions in chick sensory neurones