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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: A general scheme for allosteric activation of BK channels must consider three distinct but coupled processes: voltage sensor activation, Ca2+ binding, and channel opening. If all permutations are considered (0–4 Ca2+ bound, 0–4 voltage sensors activated, and the channel either open or closed), there are 5 × 5 × 2 = 50 possible states of the channel (Fig. 4). In the diagram, the subscripts and superscript denote the number of activated voltage sensors and the number of bound Ca2+ ions, respectively; 16 of 25 open states are “hidden” by closed states. Even that scheme could easily be extended (Horrigan et al. 1999; Rothberg and Magleby 1999). For example, if two Ca2+ ions are bound and two voltage sensors are activated, it may matter whether Ca2+ is bound to the subunits with activated voltage sensors (or whether the activated and/or Ca2+-bound subunits are opposite or adjacent).


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: A general scheme for allosteric activation of BK channels must consider three distinct but coupled processes: voltage sensor activation, Ca2+ binding, and channel opening. If all permutations are considered (0–4 Ca2+ bound, 0–4 voltage sensors activated, and the channel either open or closed), there are 5 × 5 × 2 = 50 possible states of the channel (Fig. 4). In the diagram, the subscripts and superscript denote the number of activated voltage sensors and the number of bound Ca2+ ions, respectively; 16 of 25 open states are “hidden” by closed states. Even that scheme could easily be extended (Horrigan et al. 1999; Rothberg and Magleby 1999). For example, if two Ca2+ ions are bound and two voltage sensors are activated, it may matter whether Ca2+ is bound to the subunits with activated voltage sensors (or whether the activated and/or Ca2+-bound subunits are opposite or adjacent).

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).

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