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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 1. Illustration of KCa1.1-Cav model design. (A) The voltage- and Ca2+-dependence of the KCa1.1 model is shown. Increasing [Ca2+]i results in a left-shift in voltage-dependence of KCa1.1 activation with maximal shift between 10 and 100 μM. Maximum Po is also Ca2+-dependent and increases with increasing [Ca2+]i. (B) A diagram of the KCa1.1-Cav model showing the diffusion of Ca2+ through multiple hemispherical compartments. The KCa1.1 channel is placed in a compartment and its activation calculated according to the local [Ca2+].
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Figure 1: Figure 1. Illustration of KCa1.1-Cav model design. (A) The voltage- and Ca2+-dependence of the KCa1.1 model is shown. Increasing [Ca2+]i results in a left-shift in voltage-dependence of KCa1.1 activation with maximal shift between 10 and 100 μM. Maximum Po is also Ca2+-dependent and increases with increasing [Ca2+]i. (B) A diagram of the KCa1.1-Cav model showing the diffusion of Ca2+ through multiple hemispherical compartments. The KCa1.1 channel is placed in a compartment and its activation calculated according to the local [Ca2+].

Mentions: This model generates a complex voltage- and Ca2+-dependent relationship for KCa1.1 activation, as seen in Figure 1A. In particular, increasing [Ca2+]i causes a hyperpolarized shift in KCa1.1 half-activation and increase in pmax consistent with physiological recordings of KCa1.1 channel properties.


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

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

Figure 1. Illustration of KCa1.1-Cav model design. (A) The voltage- and Ca2+-dependence of the KCa1.1 model is shown. Increasing [Ca2+]i results in a left-shift in voltage-dependence of KCa1.1 activation with maximal shift between 10 and 100 μM. Maximum Po is also Ca2+-dependent and increases with increasing [Ca2+]i. (B) A diagram of the KCa1.1-Cav model showing the diffusion of Ca2+ through multiple hemispherical compartments. The KCa1.1 channel is placed in a compartment and its activation calculated according to the local [Ca2+].
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4042487&req=5

Figure 1: Figure 1. Illustration of KCa1.1-Cav model design. (A) The voltage- and Ca2+-dependence of the KCa1.1 model is shown. Increasing [Ca2+]i results in a left-shift in voltage-dependence of KCa1.1 activation with maximal shift between 10 and 100 μM. Maximum Po is also Ca2+-dependent and increases with increasing [Ca2+]i. (B) A diagram of the KCa1.1-Cav model showing the diffusion of Ca2+ through multiple hemispherical compartments. The KCa1.1 channel is placed in a compartment and its activation calculated according to the local [Ca2+].
Mentions: This model generates a complex voltage- and Ca2+-dependent relationship for KCa1.1 activation, as seen in Figure 1A. In particular, increasing [Ca2+]i causes a hyperpolarized shift in KCa1.1 half-activation and increase in pmax consistent with physiological recordings of KCa1.1 channel properties.

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.

Show MeSH