Modeling interactions between voltage-gated Ca (2+) channels and KCa1.1 channels.
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.
Department of Cell Biology & Anatomy; Hotchkiss Brain Institute; University of Calgary; Calgary, Canada.
Jordan Dt
JD
Engbers
Department of Physiology & Pharmacology; Hotchkiss Brain Institute; University of Calgary; Calgary, Canada.
Gerald W
GW
Zamponi
Department of Cell Biology & Anatomy; Hotchkiss Brain Institute; University of Calgary; Calgary, Canada; Department of Physiology & Pharmacology; Hotchkiss Brain Institute; University of Calgary; Calgary, Canada.
Ray W
RW
Turner
D000818:Animals; D002118:Calcium / Q000378:metabolism*; D051244:Caveolin 3 / Q000378:metabolism*; D006801:Humans; D051037:Large-Conductance Calcium-Activated Potassium Channel alpha Subunits / Q000378:metabolism*; D009474:Neurons / Q000378:metabolism*; D021122:Protein Subunits / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*; D014726:Vestibular Nuclei / Q000378:metabolism*
D051244:Caveolin 3; D051037:Large-Conductance Calcium-Activated Potassium Channel alpha Subunits; D021122:Protein Subunits; D002118:Calcium
BK; Cav2.2; Cav3; KCa1.1; ion channel complex