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Commentary: a plausible model.

Jones SW - J. Gen. Physiol. (1999)

View Article: PubMed Central - PubMed

Affiliation: Department of Physiology and Biophysics, Case Western Reserve University, Cleveland, Ohio 44106, USA.

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The mechanism of BK channel gating is addressed by a recent paper in this journal (Rothberg and Magleby 1999) and by two papers in this issue (Horrigan et al. 1999; Horrigan and Aldrich 1999)... The Magleby and Aldrich labs took very different approaches, but fortunately arrive at compatible conclusions... Rothberg and Magleby 1999 examined in detail the gating of single BK channels under a limited range of conditions: +30 mV, primarily at saturating [Ca]... Regulation of BK channels is particularly complicated, because there are two fundamental regulators (Ca and voltage) instead of one... Without Ca, the BK channel is purely voltage dependent, which simplifies the situation and allows the use of established procedures for analyzing voltage-dependent gating... Without Ca, Fig. 3 reduces to a simple two-state C0–O0 model... That can produce a “crossover” of the Q–V and G–V curves, which actually has been reported for BK channels (Stefani et al. 1997)... However, Horrigan and Aldrich 1999 did not see a crossover, and suggest that the crossover results from measuring ionic and gating currents under different experimental conditions... While the Aldrich lab concentrated on BK channel gating without Ca, Rothberg and Magleby 1999 examined the opposite condition, saturating Ca... Going from kinetic data to a model is not a stereotyped, mechanical procedure, but a complex creative enterprise with ample room for different approaches... It is most comforting in this context that the two labs arrive at the same conclusion about the general structure and connectivity of the kinetic scheme underlying channel gating... But a modeler interested in (for example) the role of BK channels in AP repolarization will find little of direct use in the papers discussed here... All this will provide additional information for fine-tuning allosteric models for BK channel gating... For the time being, the models have proved useful as a framework for interpreting the effects of channel mutations (Horrigan et al. 1999).

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Mentions: Models for cooperative activation of voltage-dependent channels began with Hodgkin and Huxley 1952. In modern terminology, their K+ channel model postulated four identical and independent voltage sensors, with the channel open only if all four sensors are activated (Fig. 1), which is a straightforward mechanism for cooperativity. However, voltage sensor movement seems to be followed by a kinetically distinct channel opening step (Koren et al. 1990; Zagotta and Aldrich 1990). The resulting Fig. 2 is a subset of the full MWC model (Fig. 3). Although Fig. 3 appears to be more complicated (10 vs. 6 states), it has only one additional free parameter, an allosteric factor, which represents the energy stabilizing the open state upon movement of each voltage sensor. In terms of the underlying physical process, Fig. 3 avoids the arbitrary assumption that channel opening is completely forbidden unless all four voltage sensors are activated. For aficionados of Occam's Razor, the complexity of a model cannot be assessed by counting the number of states. The number of free parameters is a better measure—but the number of underlying physical processes is better still.


Commentary: a plausible model.

Jones SW - J. Gen. Physiol. (1999)

© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2230645&req=5

Mentions: Models for cooperative activation of voltage-dependent channels began with Hodgkin and Huxley 1952. In modern terminology, their K+ channel model postulated four identical and independent voltage sensors, with the channel open only if all four sensors are activated (Fig. 1), which is a straightforward mechanism for cooperativity. However, voltage sensor movement seems to be followed by a kinetically distinct channel opening step (Koren et al. 1990; Zagotta and Aldrich 1990). The resulting Fig. 2 is a subset of the full MWC model (Fig. 3). Although Fig. 3 appears to be more complicated (10 vs. 6 states), it has only one additional free parameter, an allosteric factor, which represents the energy stabilizing the open state upon movement of each voltage sensor. In terms of the underlying physical process, Fig. 3 avoids the arbitrary assumption that channel opening is completely forbidden unless all four voltage sensors are activated. For aficionados of Occam's Razor, the complexity of a model cannot be assessed by counting the number of states. The number of free parameters is a better measure—but the number of underlying physical processes is better still.

View Article: PubMed Central - PubMed

Affiliation: Department of Physiology and Biophysics, Case Western Reserve University, Cleveland, Ohio 44106, USA.

AUTOMATICALLY GENERATED EXCERPT
Please rate it.

The mechanism of BK channel gating is addressed by a recent paper in this journal (Rothberg and Magleby 1999) and by two papers in this issue (Horrigan et al. 1999; Horrigan and Aldrich 1999)... The Magleby and Aldrich labs took very different approaches, but fortunately arrive at compatible conclusions... Rothberg and Magleby 1999 examined in detail the gating of single BK channels under a limited range of conditions: +30 mV, primarily at saturating [Ca]... Regulation of BK channels is particularly complicated, because there are two fundamental regulators (Ca and voltage) instead of one... Without Ca, the BK channel is purely voltage dependent, which simplifies the situation and allows the use of established procedures for analyzing voltage-dependent gating... Without Ca, Fig. 3 reduces to a simple two-state C0–O0 model... That can produce a “crossover” of the Q–V and G–V curves, which actually has been reported for BK channels (Stefani et al. 1997)... However, Horrigan and Aldrich 1999 did not see a crossover, and suggest that the crossover results from measuring ionic and gating currents under different experimental conditions... While the Aldrich lab concentrated on BK channel gating without Ca, Rothberg and Magleby 1999 examined the opposite condition, saturating Ca... Going from kinetic data to a model is not a stereotyped, mechanical procedure, but a complex creative enterprise with ample room for different approaches... It is most comforting in this context that the two labs arrive at the same conclusion about the general structure and connectivity of the kinetic scheme underlying channel gating... But a modeler interested in (for example) the role of BK channels in AP repolarization will find little of direct use in the papers discussed here... All this will provide additional information for fine-tuning allosteric models for BK channel gating... For the time being, the models have proved useful as a framework for interpreting the effects of channel mutations (Horrigan et al. 1999).

Show MeSH