Role of potassium channels in regulating neuronal activity
Author: Klement, Göran
Date: 2007-10-04
Location: Lennart Nilsson-salen, Nobels väg 15A, KI Campus Solna
Time: 09.30
Department: Institutionen för neurovetenskap / Department of Neuroscience
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thesis.pdf (1.248Mb)
Abstract
The firing behaviour of excitable cells is fundamental for the
information processing in multicellular organisms, varying from single
spikes to different forms of repetitive firing. Of the many regulators,
voltage gated potassium channels play a major role.
In this thesis some aspects of the potassium channel regulation of firing
are explored. (i) The role of the channel density per se is studied in an
in silico model, (ii) the effect of a spontaneously mutated potassium
channel is studied in hippocampal slices from a mouse model, (iii) the
effect on the expression of potassium channels in general, and
consequently on the firing, by this spontaneous mutation is studied in
Xenopus oocytes, (iv) the molecular mechanisms giving the hERG channel
its specific regulatory role in cardiac firing are studied in Xenopus
oocytes and (v) the mechanisms behind the spontaneous current events in
hypothalamic neurons, shaping hypothalamic firing patterns, are studied
in mechanically isolated cells.
The computational study was based on an analysis of a hippocampal
interneuron and showed that varying the density of sodium- and potassium
channels results in qualitatively different firing patterns and threshold
dynamics, mathematically associated with different bifurcation types
(saddle node, Hopf and double-orbit).
The study of the effects of a mutated potassium channel was performed on
a megencephalic mouse model, having a truncated KV1.1 channel gene
(mceph). A patch-clamp analysis of neurons in hippocampal slices showed
that one effect of the truncation on the neurons was, in addition to an
enlarged size, a slight increase in firing frequency, compatible with a
decreased density of potassium channels.
The study of the MCEPH expression in mceph/mceph mice, showed that it
indeed was expressed, but completely retained in the ER. It was also
found that it retained other KV1 channels in the ER, reducing their
density in the plasma membrane.
The study of the molecular mechanism underlying the specific features of
hERG was performed by analysing Shaker channels with hERG emulating
substitutions. hERG is structurally characterized by aromatic residues in
the internal vestibule. We introduced one of these, tyrosine, in Shaker,
and found that it induced hERG like features, suggesting that the
tyrosine residue has a role in forming the specific hERG kinetics. In
addition, the tyrosine substitution induced an inactivation component
with inversed voltage-dependence.
The study of the spontaneous hypothalamic current events was performed
with medial preoptic area neurons and showed that the currents were due
to calcium-activated potassium channels of the SK3 subtype, triggered by
Ca2+ release from intracellular stores via ryanodine receptor channels.
Current clamp measurements showed that the spontaneous current events had
a role in shaping the firing patterns of the medial preoptic neurons.
In conclusion, this thesis work adds information on the role of potassium
channels in regulating neuronal firing at different levels. It suggests
ways to understand pharmacological effects on firing patterns, presents a
background for future studies on the trafficking of potassium channels,
suggests a novel determinant involved in hERG kinetics and indicates a
role for SK channels in neuronal firing.
List of papers:
I. Arhem P, Klement G, Blomberg C (2006). "Channel density regulation of firing patterns in a cortical neuron model." Biophys J 90(12): 4392-404. Epub 2006 Mar 24
Pubmed
II. Petersson S, Persson AS, Johansen JE, Ingvar M, Nilsson J, Klement G, Arhem P, Schalling M, Lavebratt C (2003). "Truncation of the Shaker-like voltage-gated potassium channel, Kv1.1, causes megencephaly." Eur J Neurosci 18(12): 3231-40
Pubmed
III. Persson AS, Klement G, Almgren M, Sahlholm K, Nilsson J, Petersson S, Arhem P, Schalling M, Lavebratt C (2005). "A truncated Kv1.1 protein in the brain of the megencephaly mouse: expression and interaction." BMC Neurosci 6: 65
Pubmed
IV. Klement G, Nilsson J, Århem P, Elinder F (2007). "A hERG-emulating tyrosine substitution in S6 of the Shaker channel induces an inverted inactivation." (Submitted)
V. Klement G, Druzin M, Haage D, Århem P, Johansson S (2007). "Spontaneous andcaffeine-evoked currents through SK channels in rat medial preoptic neurons." (Submitted)
I. Arhem P, Klement G, Blomberg C (2006). "Channel density regulation of firing patterns in a cortical neuron model." Biophys J 90(12): 4392-404. Epub 2006 Mar 24
Pubmed
II. Petersson S, Persson AS, Johansen JE, Ingvar M, Nilsson J, Klement G, Arhem P, Schalling M, Lavebratt C (2003). "Truncation of the Shaker-like voltage-gated potassium channel, Kv1.1, causes megencephaly." Eur J Neurosci 18(12): 3231-40
Pubmed
III. Persson AS, Klement G, Almgren M, Sahlholm K, Nilsson J, Petersson S, Arhem P, Schalling M, Lavebratt C (2005). "A truncated Kv1.1 protein in the brain of the megencephaly mouse: expression and interaction." BMC Neurosci 6: 65
Pubmed
IV. Klement G, Nilsson J, Århem P, Elinder F (2007). "A hERG-emulating tyrosine substitution in S6 of the Shaker channel induces an inverted inactivation." (Submitted)
V. Klement G, Druzin M, Haage D, Århem P, Johansson S (2007). "Spontaneous andcaffeine-evoked currents through SK channels in rat medial preoptic neurons." (Submitted)
Issue date: 2007-09-13
Rights:
Publication year: 2007
ISBN: 978-91-7357-315-3
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