Use this URL to cite or link to this record in EThOS: https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.748987
Title: Characterisation of novel cardiac and skeletal ion channels on intracellular Ca2+ stores
Author: Eberhardt, David Richard
ISNI:       0000 0004 7232 8961
Awarding Body: University of Oxford
Current Institution: University of Oxford
Date of Award: 2018
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Abstract:
Excitation-contraction (EC) coupling is the process by which Ca2+ is released from the sarcoplasmic reticulum (SR) and is fundamental to cardiac and skeletal muscle function. The SR contains many uncharacterised ion channels and proteins which may influence EC coupling and in this thesis I have investigated the biophysical properties of some of these channels. I have demonstrated that the single-channel gating and conducting properties of SR K+ channels from various mammalian species (rabbit, sheep and mouse) are very similar. I investigated the actions of possible physiological regulators of these channels and demonstrated that luminal Ca2+ and Mg2+ can block K+ flux in a voltage-dependent manner, while luminal Ca2+, Ni2+, and alkaline pH can reduce Po by additional mechanisms. I also characterised the single-channel properties of the various SR anion channels that are observed after incorporating mammalian SR vesicles into artificial membranes. The trimeric intracellular cation channels (TRIC-A and TRIC-B) and Mitsugumin 23 (MG23) are suggested to be SR cation channels. I have therefore utilised Tric-a KO and Mg23 KO mice to study SR membranes devoid of TRIC-A and MG23. Additionally, I have begun to investigate the single-channel properties of purified c. elegans TRIC-B1 and human TRIC-A. I found that SR K+ channel function was altered in SR from Tric-a KO or Mg23 KO tissue, however the underlying mechanisms for the observed changes appear to be complex. My initial studies of the purified TRIC-A and TRIC-B proteins show that they are permeable to K+, Ca2+, choline, and Cl-, properties which deviate from those of SR K+ channels from rabbit, mouse and sheep. This may reflect species differences or alterations to protein function caused during the purification process or that SR K+ channels remain an unidentified class of ion channel.
Supervisor: Sitsapesan, Rebecca Sponsor: British Heart Foundation
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID: uk.bl.ethos.748987  DOI: Not available
Keywords: Cardiovascular Science ; Drugs--Research ; Biophysics ; Ion channel ; Excitation-contraction coupling ; TRIC channel
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