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Identifier 000431910
Title Modulation of girk channels by protein kinase C
Alternative Title Ρύθμιση των GIRK καναλιών από τις πρωτεΐνικες κινάσες C
Author Επταμηνιτάκη, Χρυσοβαλάντη Γιασεμή
Thesis advisor Logothetis, Diomedes
Reviewer Καραγωγέως, Δόμνα
Ταβερναράκης, Νεκτάριος
Abstract Atrial fibrillation is a cardiac arrhythmia that affects 1 in 10 people over 65 years of age. The main characteristic of the disease is an irregular heart rate that can cause blood clots, stroke and heart failure. The etiology of atrial fibrillation has not been completely defined, however, the constitutive activity of the G-protein gated inwardly-rectifying potassium channel GIRK1/4 in atrial myocytes has been implicated. GIRK channels are critical for the maintenance of the resting membrane potential and inhibitory post-synaptic potentials in the body. One of several modulators of GIRK channel activity is protein kinase C (PKC). PKC isozymes are widely reported to inhibit GIRK channel and consist of 14 different isoforms that are divided into conventional, novel and atypical. In atrial fibrillation, an imbalance in the expression of novel PKCε has been reported. An increase in PKCε mediated augmentation of GIRK1/4 activity can explain the constitutive activity of this channel. This study evaluated the effect of novel PKCε on GIRK4 and GIRK2 homomeric channels as well as GIRK1/4 and GIRK1/2 heteromeric channels and the effect of novel PKCδ on GIRK1/2 and GIRK1/4 heteromeric channels expressed in Xenopus leavis oocytes and HEK293T cells using electrophysiological techniques. The study showed that PKCε inhibited both basal and dopamine-induced activity via the D2 receptor of GIRK2 homomeric and GIRK1/2 heteromeric channels. PKCδ also inhibited basal activity and diminished inward currents evoked through dopamine stimulation of D2 receptors in both GIRK1/2 and GIRK1/4 channels. In contrast, PKCε augmented both basal and dopamine-induced activity of GIRK4 homomeric and GIRK1/4 heteromeric channels. Furthermore, HTPDQ a small molecule that acts as a specific inhibitor of GIRK1/4 and GIRK1/2 channels was evaluated. This insight into the mechanism of augmented channel activity via novel PKC phosphorylation will assist in the research for allosteric, small-molecule channel inhibitors that balance the cardiac GIRK1/4 channel activity. Also, the extension of this study on GIRK2 channels can contribute in the development of new therapeutic approaches in diseases of the central nervous system, where GIRK2 channels are abundant.
Language English
Subject Atrial fibrillation
Protein kinase C
Κολπική μαρμαρυγή
Πρωτεϊνική κινάση C
Issue date 2020-08-05
Collection   Faculty/Department--School of Medicine--Department of Medicine--Post-graduate theses
  Type of Work--Post-graduate theses
Permanent Link https://elocus.lib.uoc.gr//dlib/1/7/2/metadata-dlib-1599561012-187978-18454.tkl Bookmark and Share
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