T-type channel interactions with calcium activated potassium channels
Date
2012-10-03
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Abstract
In this thesis we investigate the relationship between calcium activated potassium channels (KCa1.1, KCa3.1) and low voltage activated calcium channels (Cav3). KCa1.1 are known to participate in neuronal excitability through their contribution to action potential repolarization and generation of fast afterhyperpolarizing potentials (AHPs) whereas KCa3.1 channels contribute to slow AHPs. Although both KCa channel isoforms have previously been shown to be activated by calcium influx through high voltage activated calcium channels their association with Cav3 channels is unknown. First, we show that Cav3 channels are able to activate KCa1.1 channels in medial vestibular neurons and this activation takes on the voltage profile of Cav3 channels, generating KCa1.1 currents at much lower voltages than previously described for the KCa1.1-HVA complex. Using tsA-201 cells, we further characterize this relationship and show that calcium influx through Cav3.2 greatly potentiates KCa1.1 current and shifts KCa1.1 activation to hyperpolarized potentials. We also find that this complex functions in a microdomain even though the two channels are able to co-immunoprecipitate. We narrowed down the site of interaction for Cav3.2 channels on KCa1.1 as transmembrane segment S0 which has previously been shown to be involved in the binding of the KCa1.1 auxiliary β4 subunit. Surprisingly, further investigation revealed that β4 subunit is also able to bind to Cav3.2 channels and functionally decreases Cav3 current density as well as shift its activation to more positive potentials. Also, when β4 is in a complex with KCa1.1 and Cav3.2, it negates the shift in KCa1.1 activation by Cav3.2. Finally, we show that the KCa3.1 channels which previously were not thought to participate in regulating the excitability of neurons in the CNS are present in Purkinje cells and contribute to the AHP in these cells. Furthermore, we show that Cav3 channels are able to activate these KCa3.1 channels and confer a voltage dependence to their activation based on the amount of calcium influx through Cav3.We further show that these two channels physically bind through multiple sites of interaction.
This work generates a new role for the activation of KCa1.1 and KCa3.1 by Cav3.
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Biology--Molecular, Neuroscience
Citation
Rehak, R. (2012). T-type channel interactions with calcium activated potassium channels (Doctoral thesis, University of Calgary, Calgary, Canada). Retrieved from https://prism.ucalgary.ca. doi:10.11575/PRISM/28531