Engbers Jordan Dt, Zamponi Gerald W, Turner Ray W
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.
Channels (Austin). 2013 Nov-Dec;7(6):524-9. doi: 10.4161/chan.25867. Epub 2013 Jul 31.
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.
高电压激活（HVA）的Cav通道与KCa1.1通道形成复合物，通过纳米结构域相互作用实现KCa1.1电流的可靠激活。我们最近发现，低电压激活的Cav3钙通道也能形成KCa1.1-Cav3复合物。虽然免疫共沉淀研究再次支持纳米结构域相互作用，但对钙螯合剂的敏感性却与微结构域相互作用一致。KCa1.1-Cav3复合物的计算模型表明，多个Cav3通道对于激活KCa1.1通道是必要的，这可能导致KCa1.1-Cav3复合物对钙螯合剂更敏感。在此，我们扩展了该模型，并将其与KCa1.1-Cav2.2模型进行比较，以研究Cav通道电导和动力学对KCa1.1激活的作用。正如直接记录所发现的那样，Cav3通道的电压依赖性和动力学特性反映在KCa1.1电流的激活中，包括从比其他KCa1.1-Cav复合物更低的电压下的瞬时激活。KCa1.1通道的大量激活需要几个Cav3.2通道的协同活动。结合EGTA的作用，这些结果表明，尽管KCa1.1和Cav3通道之间存在物理关联，但几个KCa1.1-Cav3复合物的Ca(2+)结构域需要协同作用以产生足够的[Ca(2+)]i。相比之下，Cav2.2通道激活KCa1.1通道的效率是其两倍，单个KCa1.1-Cav2.2复合物就足够了。然而，尽管Cav3通道产生小的瞬时电流，但如果多个复合物通过微结构域相互作用协同作用，Cav3通道对KCa1.1活性的调节也是可能的。
