T-type channel interactions with calcium activated potassium channels

Rehak, Renata

T-type channel interactions with calcium activated potassium channels

atmire.migration.oldid	397
dc.contributor.advisor	Zamponi, Gerald
dc.contributor.author	Rehak, Renata
dc.date.accessioned	2012-10-03T15:31:20Z
dc.date.available	2012-11-13T08:01:46Z
dc.date.issued	2012-10-03
dc.date.submitted	2012	en
dc.description.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.	en_US
dc.identifier.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	en_US
dc.identifier.doi	http://dx.doi.org/10.11575/PRISM/28531
dc.identifier.uri	http://hdl.handle.net/11023/262
dc.language.iso	eng
dc.publisher.faculty	Graduate Studies
dc.publisher.institution	University of Calgary	en
dc.publisher.place	Calgary	en
dc.rights	University of Calgary graduate students retain copyright ownership and moral rights for their thesis. You may use this material in any way that is permitted by the Copyright Act or through licensing that has been assigned to the document. For uses that are not allowable under copyright legislation or licensing, you are required to seek permission.
dc.subject	Biology--Molecular
dc.subject	Neuroscience
dc.subject.classification	t-type channels	en_US
dc.subject.classification	Potassium channels	en_US
dc.subject.classification	calcium	en_US
dc.title	T-type channel interactions with calcium activated potassium channels
dc.type	doctoral thesis
thesis.degree.discipline	Neuroscience
thesis.degree.grantor	University of Calgary
thesis.degree.name	Doctor of Philosophy (PhD)
ucalgary.item.requestcopy	true