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Title: Properties of voltage-gated Na+ channels in pancreatic beta-cells
Author: Godazgar, Mahdieh
ISNI:       0000 0004 7652 4062
Awarding Body: University of Oxford
Current Institution: University of Oxford
Date of Award: 2017
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Nav channels in rodent β-cells predominantly exhibit a hyperpolarised voltage-dependence of inactivation, which is so characteristic that it can be used for functional identification of β-cells. A smaller Na+ current component (10-15%) also exists that inactivates over physiological membrane potentials and contributes to action potential firing. It has been proposed that the currents contributing to inactivation over vastly different membrane potentials reflect the contribution of different Nav α-subunits. The aim of this thesis was to investigate the contribution of individual Nav channel α-subunits to the behaviour of Nav current inactivation in β-cells and to gain insight into the underlying mechanism(s) of channel regulation. TTX-resistant variants of the Nav subunits found in β-cells (NaV1.3, NaV1.6 and NaV1.7) were used to isolate currents from individual α-subunits expressed in insulin-secreting Ins1 cells and in non-β-cells (including HEK, CHO and αTC1-6 cells). Nav1.7 inactivated at 15-20mV more negative membrane potentials than Nav1.3 and Nav1.6 in Ins1 cells. Meanwhile, all Nav subunits inactivated at ~20-30mV more negative membrane potentials in Ins1 cells than in HEK, CHO or αTC1-6 cells reflecting α-subunit and cell-specific differences in the inactivation of Nav channels. In Ins1 and primary β-cells, but never in the other cell types, widely different components of Nav inactivation (separated by 30 mV) were also observed following expression of a single type of Nav α-subunit. The more positive component exhibited a voltage-dependence of inactivation similar to that found in HEK/CHO cells. The more negative inactivation in Ins1 cells does not involve a diffusible intracellular factor because the difference between Ins1 and CHO persisted after excision of the membrane. We propose that biphasic Nav inactivation in insulin-secreting cells reflects insertion of channels in membrane domains that differ with regard to lipid and/or membrane protein composition.
Supervisor: Rorsman, Patrik ; Chibalina, Margarita Sponsor: Radcliffe Department of Medicine Scholars Programme
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available