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Targeting the voltage-gated calcium channels as treatment for type 2 diabetes

Buda, Pawel LU (2015) In Lund University Faculty of Medicine Doctoral Dissertation Series 2015:97.
Abstract
L-type voltage-gated Ca2+ channels are expressed in the plasma membrane of muscles, neurons and endocrine cells where they serve as conductors of signals regulating cellular responses to changes in environment. Malfunctions of channels, as well as deregulations of their activity underlie numerous disorders and diseases commonly called channelopathies. In β-cells Ca2+ channels are central players for insulin secretion. In response to glucose, as well as other nutrients, channels mediate influx of extracellular Ca2+, which triggers insulin secretion. In spite of the fact that inadequate insulin secretion causes type 2 diabetes (T2D) and that some successful therapies for this disease target Ca2+ channels, there is still insufficient evidence... (More)
L-type voltage-gated Ca2+ channels are expressed in the plasma membrane of muscles, neurons and endocrine cells where they serve as conductors of signals regulating cellular responses to changes in environment. Malfunctions of channels, as well as deregulations of their activity underlie numerous disorders and diseases commonly called channelopathies. In β-cells Ca2+ channels are central players for insulin secretion. In response to glucose, as well as other nutrients, channels mediate influx of extracellular Ca2+, which triggers insulin secretion. In spite of the fact that inadequate insulin secretion causes type 2 diabetes (T2D) and that some successful therapies for this disease target Ca2+ channels, there is still insufficient evidence to consider this disease as channelopathy. Recently, our research group demonstrated that β-cells from T2D individuals carry mutations in L-type Ca2+ channel gene, which impair expression of this channel and increase the risk for T2D. This study instigated further curiosity as to how physiological stimuli regulate the surface expression of L-type Ca2+ channels and whether this regulation is altered in T2D with consequences for cellular homeostasis, and survival. Present thesis addresses these questions.

The first study identified a mechanism, by which β-cells regulate surface expression of L-type Ca2+ channels in response to glucose and activation of channels. Stimulation of clonal, insulin-secreting cells caused evacuation of L-type channels from the plasma membrane to the cytosol. This effect was reversible after cessation of the stimulation and was mediated by eIF3e, the novel regulatory protein of Ca2+ channels. Ablation of eIF3e abolished channel internalization, thereby rendered cells prone to Ca2+ overload.

The second study showed that in β-cells from T2D human donors the number of L-type channels at the plasma membrane is elevated and that internalization mechanism is not functional. These two abnormalities cause cells susceptible to toxicity of glucose due to Ca2+ overload mediated by L-type Ca2+ channels entrapped in the plasma membrane.

The third study delineated mechanism, through which Ca2+ overload contributes to the loss of β-cell mass observed in T2D in the presence of elevated levels of glucose and free fatty acids, the characteristic milieu for this disease. Overly active L-type Ca2+ channels activated Nur77 and Nor-1 proteins, which inhibited autophagy, the crucial process rescuing cells from cytotoxic stresses exerted by glucose and free fatty acids.

Taken together, this thesis shows that L-type Ca2+ channels determine vitality of β-cells and that deregulation of expression of these channels occurs in T2D contributing to progression of the disease. (Less)
Please use this url to cite or link to this publication:
author
supervisor
opponent
  • Professor Tengholm, Anders, Uppsala University, Sweden
organization
publishing date
type
Thesis
publication status
published
subject
keywords
autophagy, apoptosis, calcium channels, Type 2 Diabetes
in
Lund University Faculty of Medicine Doctoral Dissertation Series
volume
2015:97
pages
54 pages
publisher
Islet patophysiology, Clinical Sciences, Malmö
defense location
Lilla Aulan, MFC, Jan Waldenströms gata 1, Skånes universitetssjukhus i Malmö.
defense date
2015-10-01 09:00
ISSN
1652-8220
ISBN
978-91-7619-176-7
language
English
LU publication?
yes
id
2f4c8fda-8cb6-4aba-b275-0a0fde77f7c5 (old id 7852270)
date added to LUP
2015-09-09 08:54:53
date last changed
2016-09-19 08:44:46
@phdthesis{2f4c8fda-8cb6-4aba-b275-0a0fde77f7c5,
  abstract     = {L-type voltage-gated Ca2+ channels are expressed in the plasma membrane of muscles, neurons and endocrine cells where they serve as conductors of signals regulating cellular responses to changes in environment. Malfunctions of channels, as well as deregulations of their activity underlie numerous disorders and diseases commonly called channelopathies. In β-cells Ca2+ channels are central players for insulin secretion. In response to glucose, as well as other nutrients, channels mediate influx of extracellular Ca2+, which triggers insulin secretion. In spite of the fact that inadequate insulin secretion causes type 2 diabetes (T2D) and that some successful therapies for this disease target Ca2+ channels, there is still insufficient evidence to consider this disease as channelopathy. Recently, our research group demonstrated that β-cells from T2D individuals carry mutations in L-type Ca2+ channel gene, which impair expression of this channel and increase the risk for T2D. This study instigated further curiosity as to how physiological stimuli regulate the surface expression of L-type Ca2+ channels and whether this regulation is altered in T2D with consequences for cellular homeostasis, and survival. Present thesis addresses these questions.<br/><br>
The first study identified a mechanism, by which β-cells regulate surface expression of L-type Ca2+ channels in response to glucose and activation of channels. Stimulation of clonal, insulin-secreting cells caused evacuation of L-type channels from the plasma membrane to the cytosol. This effect was reversible after cessation of the stimulation and was mediated by eIF3e, the novel regulatory protein of Ca2+ channels. Ablation of eIF3e abolished channel internalization, thereby rendered cells prone to Ca2+ overload.<br/><br>
The second study showed that in β-cells from T2D human donors the number of L-type channels at the plasma membrane is elevated and that internalization mechanism is not functional. These two abnormalities cause cells susceptible to toxicity of glucose due to Ca2+ overload mediated by L-type Ca2+ channels entrapped in the plasma membrane.<br/><br>
The third study delineated mechanism, through which Ca2+ overload contributes to the loss of β-cell mass observed in T2D in the presence of elevated levels of glucose and free fatty acids, the characteristic milieu for this disease. Overly active L-type Ca2+ channels activated Nur77 and Nor-1 proteins, which inhibited autophagy, the crucial process rescuing cells from cytotoxic stresses exerted by glucose and free fatty acids.<br/><br>
Taken together, this thesis shows that L-type Ca2+ channels determine vitality of β-cells and that deregulation of expression of these channels occurs in T2D contributing to progression of the disease.},
  author       = {Buda, Pawel},
  isbn         = {978-91-7619-176-7},
  issn         = {1652-8220},
  keyword      = {autophagy,apoptosis,calcium channels,Type 2 Diabetes},
  language     = {eng},
  pages        = {54},
  publisher    = {Islet patophysiology, Clinical Sciences, Malmö},
  school       = {Lund University},
  series       = {Lund University Faculty of Medicine Doctoral Dissertation Series},
  title        = {Targeting the voltage-gated calcium channels as treatment for type 2 diabetes},
  volume       = {2015:97},
  year         = {2015},
}