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Modeling interactions between voltage-gated Ca (2+) channels and KCa1.1 channels.

Engbers JD, Zamponi GW, Turner RW - Channels (Austin) (2013)

Bottom Line: We recently found that low voltage-activated Cav3 calcium channels also create KCa1.1-Cav3 complexes.Combined with the effect of EGTA, these results suggest that the Ca (2+) domains of several KCa1.1-Cav3 complexes need to cooperate to generate sufficient [Ca (2+)]i, despite the physical association between KCa1.1 and Cav3 channels.By comparison, Cav2.2 channels were twice as effective at activating KCa1.1 channels and a single KCa1.1-Cav2.2 complex would be self-sufficient.

View Article: PubMed Central - PubMed

Affiliation: Department of Cell Biology & Anatomy; Hotchkiss Brain Institute; University of Calgary; Calgary, Canada.

ABSTRACT
High voltage-activated (HVA) Cav channels form complexes with KCa1.1 channels, allowing reliable activation of KCa1.1 current through a nanodomain interaction. We recently found that low voltage-activated Cav3 calcium channels also create KCa1.1-Cav3 complexes. While coimmunoprecipitation studies again supported a nanodomain interaction, the sensitivity to calcium chelating agents was instead consistent with a microdomain interaction. A computational model of the KCa1.1-Cav3 complex suggested that multiple Cav3 channels were necessary to activate KCa1.1 channels, potentially causing the KCa1.1-Cav3 complex to be more susceptible to calcium chelators. Here, we expanded the model and compared it to a KCa1.1-Cav2.2 model to examine the role of Cav channel conductance and kinetics on KCa1.1 activation. As found for direct recordings, the voltage-dependent and kinetic properties of Cav3 channels were reflected in the activation of KCa1.1 current, including transient activation from lower voltages than other KCa1.1-Cav complexes. Substantial activation of KCa1.1 channels required the concerted activity of several Cav3.2 channels. Combined with the effect of EGTA, these results suggest that the Ca (2+) domains of several KCa1.1-Cav3 complexes need to cooperate to generate sufficient [Ca (2+)]i, despite the physical association between KCa1.1 and Cav3 channels. By comparison, Cav2.2 channels were twice as effective at activating KCa1.1 channels and a single KCa1.1-Cav2.2 complex would be self-sufficient. However, even though Cav3 channels generate small, transient currents, the regulation of KCa1.1 activity by Cav3 channels is possible if multiple complexes cooperate through microdomain interactions.

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Figure 2. Voltage-dependent properties of KCa1.1-Cav complexes with multiple Cav channels. (A) KCa1.1-Cav3.2 and KCa1.1-Cav2.2 complexes exhibit different voltage dependencies. KCa1.1-Cav3.2 complexes (1–8 channels at 20 nm, left) show significant activation in low voltage ranges. KCa1.1-Cav2.2 complexes (1–8 channels at 20 nm, right) only show activation for voltages more positive than -40 mV. KCa1.1-Ca2.2(8×; 20 nm) has a greater maximal activation than the KCa1.1-Cav3.2(8×, 20 nm) model. (B) Increasing the distance between the KCa1.1 and Cav3.2 or Cav2.2 channels to 40 nm significantly decreases the maximal activation of KCa1.1 channels over all voltages. (C) Plots of the maximal PO for Cav3.2 (left) or Cav2.2 (right) channels when different numbers of channels are included in the complex. Dashed line indicates the peak Po for a single Cav2.2 channel, for reference. KCa1.1-Cav2.2 complexes generate greater KCa1.1 activation when compared with KCa1.1-Cav3.2 complexes with the same number of channels.
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Figure 2: Figure 2. Voltage-dependent properties of KCa1.1-Cav complexes with multiple Cav channels. (A) KCa1.1-Cav3.2 and KCa1.1-Cav2.2 complexes exhibit different voltage dependencies. KCa1.1-Cav3.2 complexes (1–8 channels at 20 nm, left) show significant activation in low voltage ranges. KCa1.1-Cav2.2 complexes (1–8 channels at 20 nm, right) only show activation for voltages more positive than -40 mV. KCa1.1-Ca2.2(8×; 20 nm) has a greater maximal activation than the KCa1.1-Cav3.2(8×, 20 nm) model. (B) Increasing the distance between the KCa1.1 and Cav3.2 or Cav2.2 channels to 40 nm significantly decreases the maximal activation of KCa1.1 channels over all voltages. (C) Plots of the maximal PO for Cav3.2 (left) or Cav2.2 (right) channels when different numbers of channels are included in the complex. Dashed line indicates the peak Po for a single Cav2.2 channel, for reference. KCa1.1-Cav2.2 complexes generate greater KCa1.1 activation when compared with KCa1.1-Cav3.2 complexes with the same number of channels.

Mentions: We first compared the activation properties of KCa1.1 by a single Cav3.2 or Cav2.2 channel as a Ca2+ source at a fixed distance of 20 nm, which would correspond to direct juxtaposition of a Cav and KCa1.1 channel. Cav3.2 channels have a small single channel conductance (1.7 pS) and exhibit rapid and complete inactivation.6,8 At a distance of 20 nm from KCa1.1 in the model, a single Cav3.2 channel only caused a slight increase in the open probability (Po) of the KCa1.1 channel, reaching just 0.06 of maximal conductance (Fig. 2A, right, dark blue). Cav2.2 channels have a much higher single channel conductance, maximal Po, and inactivate slowly.5,6,10,12 A single Cav2.2 channel at 20 nm distance from a KCa1.1 channel was thus able to increase the KCa1.1 Po to 0.14, or twice that of a single Cav3.2 channel (Fig. 2A, left).


Modeling interactions between voltage-gated Ca (2+) channels and KCa1.1 channels.

Engbers JD, Zamponi GW, Turner RW - Channels (Austin) (2013)

Figure 2. Voltage-dependent properties of KCa1.1-Cav complexes with multiple Cav channels. (A) KCa1.1-Cav3.2 and KCa1.1-Cav2.2 complexes exhibit different voltage dependencies. KCa1.1-Cav3.2 complexes (1–8 channels at 20 nm, left) show significant activation in low voltage ranges. KCa1.1-Cav2.2 complexes (1–8 channels at 20 nm, right) only show activation for voltages more positive than -40 mV. KCa1.1-Ca2.2(8×; 20 nm) has a greater maximal activation than the KCa1.1-Cav3.2(8×, 20 nm) model. (B) Increasing the distance between the KCa1.1 and Cav3.2 or Cav2.2 channels to 40 nm significantly decreases the maximal activation of KCa1.1 channels over all voltages. (C) Plots of the maximal PO for Cav3.2 (left) or Cav2.2 (right) channels when different numbers of channels are included in the complex. Dashed line indicates the peak Po for a single Cav2.2 channel, for reference. KCa1.1-Cav2.2 complexes generate greater KCa1.1 activation when compared with KCa1.1-Cav3.2 complexes with the same number of channels.
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Figure 2: Figure 2. Voltage-dependent properties of KCa1.1-Cav complexes with multiple Cav channels. (A) KCa1.1-Cav3.2 and KCa1.1-Cav2.2 complexes exhibit different voltage dependencies. KCa1.1-Cav3.2 complexes (1–8 channels at 20 nm, left) show significant activation in low voltage ranges. KCa1.1-Cav2.2 complexes (1–8 channels at 20 nm, right) only show activation for voltages more positive than -40 mV. KCa1.1-Ca2.2(8×; 20 nm) has a greater maximal activation than the KCa1.1-Cav3.2(8×, 20 nm) model. (B) Increasing the distance between the KCa1.1 and Cav3.2 or Cav2.2 channels to 40 nm significantly decreases the maximal activation of KCa1.1 channels over all voltages. (C) Plots of the maximal PO for Cav3.2 (left) or Cav2.2 (right) channels when different numbers of channels are included in the complex. Dashed line indicates the peak Po for a single Cav2.2 channel, for reference. KCa1.1-Cav2.2 complexes generate greater KCa1.1 activation when compared with KCa1.1-Cav3.2 complexes with the same number of channels.
Mentions: We first compared the activation properties of KCa1.1 by a single Cav3.2 or Cav2.2 channel as a Ca2+ source at a fixed distance of 20 nm, which would correspond to direct juxtaposition of a Cav and KCa1.1 channel. Cav3.2 channels have a small single channel conductance (1.7 pS) and exhibit rapid and complete inactivation.6,8 At a distance of 20 nm from KCa1.1 in the model, a single Cav3.2 channel only caused a slight increase in the open probability (Po) of the KCa1.1 channel, reaching just 0.06 of maximal conductance (Fig. 2A, right, dark blue). Cav2.2 channels have a much higher single channel conductance, maximal Po, and inactivate slowly.5,6,10,12 A single Cav2.2 channel at 20 nm distance from a KCa1.1 channel was thus able to increase the KCa1.1 Po to 0.14, or twice that of a single Cav3.2 channel (Fig. 2A, left).

Bottom Line: We recently found that low voltage-activated Cav3 calcium channels also create KCa1.1-Cav3 complexes.Combined with the effect of EGTA, these results suggest that the Ca (2+) domains of several KCa1.1-Cav3 complexes need to cooperate to generate sufficient [Ca (2+)]i, despite the physical association between KCa1.1 and Cav3 channels.By comparison, Cav2.2 channels were twice as effective at activating KCa1.1 channels and a single KCa1.1-Cav2.2 complex would be self-sufficient.

View Article: PubMed Central - PubMed

Affiliation: Department of Cell Biology & Anatomy; Hotchkiss Brain Institute; University of Calgary; Calgary, Canada.

ABSTRACT
High voltage-activated (HVA) Cav channels form complexes with KCa1.1 channels, allowing reliable activation of KCa1.1 current through a nanodomain interaction. We recently found that low voltage-activated Cav3 calcium channels also create KCa1.1-Cav3 complexes. While coimmunoprecipitation studies again supported a nanodomain interaction, the sensitivity to calcium chelating agents was instead consistent with a microdomain interaction. A computational model of the KCa1.1-Cav3 complex suggested that multiple Cav3 channels were necessary to activate KCa1.1 channels, potentially causing the KCa1.1-Cav3 complex to be more susceptible to calcium chelators. Here, we expanded the model and compared it to a KCa1.1-Cav2.2 model to examine the role of Cav channel conductance and kinetics on KCa1.1 activation. As found for direct recordings, the voltage-dependent and kinetic properties of Cav3 channels were reflected in the activation of KCa1.1 current, including transient activation from lower voltages than other KCa1.1-Cav complexes. Substantial activation of KCa1.1 channels required the concerted activity of several Cav3.2 channels. Combined with the effect of EGTA, these results suggest that the Ca (2+) domains of several KCa1.1-Cav3 complexes need to cooperate to generate sufficient [Ca (2+)]i, despite the physical association between KCa1.1 and Cav3 channels. By comparison, Cav2.2 channels were twice as effective at activating KCa1.1 channels and a single KCa1.1-Cav2.2 complex would be self-sufficient. However, even though Cav3 channels generate small, transient currents, the regulation of KCa1.1 activity by Cav3 channels is possible if multiple complexes cooperate through microdomain interactions.

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