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Search command : Author="Επταμηνιτάκη"
And Author="Χρυσοβαλάντη"
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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
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Επταμηνιτάκη, Χρυσοβαλάντη Γιασεμή
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Thesis advisor
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Logothetis, Diomedes
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Reviewer
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Καραγωγέως, Δόμνα
Ταβερναράκης, Νεκτάριος
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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.
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Language |
English |
Subject |
Atrial fibrillation |
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Protein kinase C |
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Κολπική μαρμαρυγή |
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Πρωτεϊνική κινάση C |
Issue date |
2020-08-05 |
Collection
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School/Department--School of Medicine--Department of Medicine--Post-graduate theses
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Type of Work--Post-graduate theses
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Permanent Link |
https://elocus.lib.uoc.gr//dlib/1/7/2/metadata-dlib-1599561012-187978-18454.tkl
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Views |
266 |