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Modulation of Gap Junctions and the Intracellular Resistance Pathway in Guinea-Pig Myocardium.

Salvage, Samantha. (2013) Modulation of Gap Junctions and the Intracellular Resistance Pathway in Guinea-Pig Myocardium. Doctoral thesis, University of Surrey (United Kingdom)..

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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 Rj. This work aimed to demonstrate the role of Cn-dependent pathways in modulating Rj when intracellular [Ca2+] was raised, any role of CaMkinase-ll (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 μM) and calcineurin auto-inhibitory peptide (50 μM). CaMKII 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 [Ca2+] 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 dephosphorylated Cx43 typical of increased Rj and GJ uncoupling. These novel findings identify a potential pathway for investigation and clinical manipulation in cardiac pathologies consequent on an elevated intracellular [Ca2+].

Item Type: Thesis (Doctoral)
Divisions : Theses
Authors : Salvage, Samantha.
Date : 2013
Additional Information : Thesis (Ph.D.)--University of Surrey (United Kingdom), 2013.
Depositing User : EPrints Services
Date Deposited : 14 May 2020 14:03
Last Modified : 14 May 2020 14:12

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