Use this URL to cite or link to this record in EThOS: http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.604348
Title: Modulation of gap junctions and the intracellular resistance pathway in guinea-pig myocardium
Author: Salvage, Samantha
Awarding Body: University of Surrey
Current Institution: University of Surrey
Date of Award: 2013
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Abstract:
Myocardial intracellular communication via gap junctions (GJ) is fundamental to action potential (AP) propagation facilitating ordered atrial and ventricular contraction. Cardiac arrhythmias can be initiated by increased intracellular (Ca2+), and are associated with abnormal AP conduction due to increased intracellular resistivity (RI) and, specifically, gap junction resistivity (Rj), Recent evidence suggested the Ca2+/calmodulin (CaM)-dependent protein phosphatase calcineurin (Cn) slowed conduction, possibly through increasing RI. This work aimed to demonstrate the role of Cn-dependent pathways in modulating RJ when intracellular [(a2+] was raised, any role of CaMkinase-1I (CaMKII) was also assessed. Rj was measured by longitudinal impedance measurements using atrial and ventricular guinea-pig preparations in control and low-Na Tyrode's solutions, with or without the Cn inhibitors cyclosporin-A (5 IlM) and calcineurin auto-inhibitory peptide (50IlM). CaMKl1 was also assessed by using its inhibitor KN-93. Western blot and immunohistochemical confocal analyses, with Cx40, total Cx43 and phospho-specific Cx43 antibodies, were performed to quantify alterations in GJ abundance, localisation and phosphorylation state. The study established that a raised intracellular {Ca 2+J increased RJ by a CnA-dependent pathway, but CaMKII had no role. In atrial tissue RJ increase was associated with a Cn-dependent increase of Cx43-S368 phosphorylation in addition to a Cn-independent increase of Cx40 abundance. By contrast, ventricular myocardium showed an overall increase of de phosphorylated Cx43 typical of increased Ri and GJ uncoupling. These novel findings identify a potential pathway for investigation and clinical manipulation in cardiac pathologies consequent on an elevated intracellular [Ca 2+].
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID: uk.bl.ethos.604348  DOI: Not available
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