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CNS &
Neurological Disorders -Drug Targets
ISSN: 1871-5273
CNS & Neurological Disorders
- Drug Targets
Volume 5, Number 6, December 2006
Contents
T-Type Calcium Channels in Health and Disease
Guest Editor: Slobodan M. Todorovic
Editorial Pp. 569
The Role of T-Channels in the Generation of Thalamocortical
Rhythms Pp. 571-585
Diego Contreras
[Abstract]
Pharmacology and Drug Discovery for T-Type Calcium
Channels Pp. 587-603
Joseph G. McGivern
[Abstract]
Molecular Biology of T-Type Calcium Channels
Pp. 605-609
E. Perez-Reyes and P. Lory
[Abstract]
Modulation of Neuronal T-Type Calcium Channels
Pp. 611-627
R.C. Lambert, T. Bessaih and N. Leresche
[Abstract]
Genetic Studies on the Role of T-Type Ca2+
Channels in Sleep and Absence Epilepsy Pp. 629-638
Hee-Sup Shin, Jungryun Lee and Inseon Song
[Abstract]
The Role of T-Type Calcium Channels in Peripheral
and Central Pain Processing Pp. 639-653
Slobodan M. Todorovic and Vesna Jevtovic-Todorovic
[Abstract]
Density is Density – On the Relation Between
Quantity of T-Type Ca2+
Channels and Neuronal Electrical Behavior Pp. 655-662
E. Chorev, Y. Manor and Y. Yarom
[Abstract]
Abstracts
[Back to top]
Editorial
Voltage-gated calcium (Ca2+) channels are heteromeric
complexes found in the plasma membrane of virtually all cell
types and show a high level of electrophysiological and pharmacological
diversity. On the basis of the membrane potential at which
they activate, these channels are subdivided into high voltage-activated
(HVA) and low voltage-activated (LVA) or transient (T-type)
Ca2+ channels. These channels in nerve tissue play
a central role in controlling cell excitability and neurotransmitter
release.
Whereas it has been known that HVA-type Ca2+ currents
arise from multiple forms of Ca2+ channels with
distinct pharmacological properties, the extent to which T-type
Ca2+ current arises from multiple Ca2+
channel subtypes became clear more recently. Recent cloning
of α1
subunits of T-type channels has revealed the existence of
at least three subtypes named G (Cav3.1), H (Cav3.2)
and I (Cav3.3) that are likely to contribute to
the heterogeneity of T-type Ca2+ currents observed
in native cells.
Although T-type currents are relatively easy to study in isolation
from other Ca2+ current components by virtue of
their unique biophysical properties such as activation, inactivation
and deactivation, pharmacological tools for identification
and investigation of T-type currents are limited. However,
recent cloning of T-type calcium channels and development
of more selective blockers of T-type channels allowed better
understanding of the roles of these channels in control of
the variety of physiological functions in the central nervous
system (CNS) and peripheral tissues. Thus, the major roles
for the T-type channels in neurons include promotion of Ca2+-dependent
burst firing, low-amplitude intrinsic neuronal oscillations,
promotion of Ca2+ entry and boosting of synaptic
signals. Furthermore, T-type currents in the thalamus appear
to play a role in seizure susceptibility and initiation and
T-type channels in peripheral sensory neurons play an important
role in boosting of pain signals.
In this review, we summarize the most recent evidence of the
multiple roles of T-type calcium channels in neurons and their
role in various physiological and pathological conditions
such as pain disorders, absence seizure and sleep disorders.
Better definition of the pharmacological properties of different
T-type current variants in these cells is of major importance
in understanding the physiological role of these currents
and their participation in the effects of clinical drugs.
Furthermore, future functional studies and development of
selective blockers of T-type channels will allow better understanding
of their role in pathological processes of the central and
peripheral nervous system as well.
Slobodan M. Todorovic
University of Virginia Health System
Charlottesville
VA 22908
USA
E-mail: st9d@virginia.edu
[Back to top]
The Role of T-Channels in the Generation of Thalamocortical
Rhythms
Diego Contreras
The presence of T-channels in thalamic cells allows for
the generation of rhythmic bursts of spikes and the existence
of two firing modes in thalamic cells: tonic and bursting.
This intrinsic electrophysiological property has fundamental
consequences for the functional properties of the thalamus
across waking and sleep stages and is centrally implicated
in a growing number of pathological states. Rhythmic bursting
brings about highly synchronized activity throughout corticothalamic
circuits which is incompatible with the relay of information
through the thalamus. Understanding the conditions that determine
the change in firing mode of thalamic cells as well as the
role of bursting in the generation of synchronized oscillations
is critical to understand the function of the thalamus. The
functional properties of T-channels and the resulting low
threshold spike are discussed here with emphasis on the differences
in the bursting properties of reticular thalamic and thalamocortical
neurons. The role of thalamic bursting in the generation of
sleep oscillations and their specific sequence during slow
wave sleep will also be discussed.
[Back to top]
Pharmacology and Drug Discovery for T-Type Calcium
Channels
Joseph G. McGivern
Voltage-gated calcium channels are found in the plasma membrane
of many excitable and non-excitable cells. When open, they
permit influx of calcium, which acts as a second messenger
to initiate diverse physiological cellular processes. Ten
unique α1
subunits, grouped in three families (Cav1, Cav2,
and Cav3), encode biophysically and pharmacologically
distinct low-voltage-activated T-type and high-voltage-activated
L-type, N-type, P/Q-type, and R-type calcium channels. T-type
calcium channels are found in neurons where they generate
low-threshold calcium spikes and influence action potential
firing patterns, in heart cells where they influence pacemaking
and impulse conduction, in smooth muscle cells where they
regulate myogenic tone and proliferation, in endocrine cells
where they regulate hormone secretion, and in sperm where
they regulate the acrosome reaction. Validation of T-type
calcium channels in disease is based on an abundance of data
pertaining to clinical efficacy of T-type calcium channel
blockers in certain human conditions as well as information
relating to the distribution, functional properties, and physiological
roles of these channels. This review focuses on the cellular
and molecular pharmacology of T-type calcium channels. It
describes novel research approaches to discover potent and
selective T-type calcium channel modulators as potential drugs
for treating human disease and as tools for understanding
better the physiological roles of T-type calcium channels.
[Back to top]
Molecular Biology of T-Type Calcium Channels
E. Perez-Reyes and P. Lory
This review summarizes recent progress on the molecular biology
of low voltage-gated, T-type, calcium channels. The genes
encoding these channels were identified by molecular cloning
of cDNAs that were similar in sequence to the a1 subunit of
high voltage-activated Ca2+ channels. Three T-channel
genes were identified: CACNA1G, encoding Cav3.1;
CACNA1H, encoding Cav3.2; and CACNA1I,
encoding Cav3.3. Recent studies have focused on
how these genes give rise to alternatively spliced transcripts,
and how this splicing affects channel activity. A second area
of focus is on how single nucleotide polymorphisms (SNPs)
alter channel activity. Based on their distribution in thalamic
nuclei, coupled with the physiological role they play in thalamic
oscillations, leads to the conclusion that SNPs in T-channel
genes may contribute to neurological disorders characterized
by thalamocortical dysrhythmia, such as generalized epilepsy.
[Back to top]
Modulation of Neuronal T-Type Calcium Channels
R.C. Lambert, T. Bessaih and N. Leresche
As T-type calcium channels open near resting membrane potential
and markedly influence neuronal excitability their activity
needs to be tightly regulated. Few neuronal T-current regulations
have been described so far, but interestingly some of them
involve unusual mechanisms like G protein-independent but
receptor-coupled modulation, while the use of recombinant
channels has established both a direct action of Gβγ
subunits, anandamide, arachidonic acid and a phophorylation
process by CaMKII. Nearly all reported types of modulation
involve Cav3.2 channels while no regulation of Cav3.1 has
been reported, a difference that may originate from diversities
in the intracellular loop connecting the II and III domains
of the two isotypes.
The search for T-current regulators requires taking into account
their peculiar activation properties, since a close link may
exist between the channel conformation and its modulation.
Indeed, in thalamocortical neurons a phosphorylation-mediated
regulation of the amplitude of the T-current has been shown
to be highly dependent upon the state of the channel and only
to become apparent when the channels are in the voltage range
close to neuronal resting membrane potential.
[Back to top]
Genetic Studies on the Role of T-Type Ca2+
Channels in Sleep and Absence Epilepsy
Hee-Sup Shin, Jungryun Lee and Inseon Song
Thalamocortical neurons in mammals fire action potentials
in two different modes, burst or tonic, depending on the cellular
state. The burst firing is driven by the low threshold Ca2+
spike that is generated by Ca2+ influx through
T-type Ca2+ channels, and has long been implicated
in the pathogenesis of absence epilepsy and the regulation
of sleep rhythms. The recent availability of the knock-out
mice for the α1G
locus, encoding the predominant form of T-type channels in
thalamocortical neurons, has provided an opportunity to examine
those ideas at the level of organism. In this review we will
describe recent results demonstrating the essential role of
thalamic bursts in certain forms of absence seizures and in
some of the sleep rhythms. Available information so far reveals
the sensory gating role of thalamic bursts, and thus of α1G
T-type channels. Understanding of the molecular targets involved
in pathophysiological mechanisms will help develop drugs to
control those pathological states.
[Back to top]
The Role of T-Type Calcium Channels in Peripheral
and Central Pain Processing
Slobodan M. Todorovic and Vesna Jevtovic-Todorovic
It is well established that the voltage-gated calcium (Ca2+)
channels can modulate neuronal activity in the peripheral
and central nervous system causing a variety of behavioral
and neuro-endocrine changes in humans and animals. While much
attention was focused on the modulation of high voltage-activated
(HVA)-type Ca2+ channels, the role of low voltage-activated
(LVA) or transient (T) type Ca2+ channels in sensory
processing, and in particular pain processing (nociception)
is much less certain. However, recent evidence strongly suggests
that modulation of both central and peripheral T-type Ca2+
channels influences somatic and visceral nociceptive inputs
and that modulation of T-type Ca2+ currents results
in significant alteration of pain threshold in a variety of
animal pain models. Therefore, T-type Ca2+ channels
in peripheral and central neurons, although previously unrecognized,
may be important targets for analgesic therapeutic agents
including endogenous compounds. Currently available pain therapies
remain insufficient with limited efficacy and numerous side
effects. Hence, studies of selective and potent modulators
of neuronal T-type Ca2+ channels may greatly aid
in revealing roles for these channels in sensory pathways
(nociception in particular) and in the development of novel
and potentially more effective and safer pain therapies. In
the present review, we summarize the putative role of peripheral
and central T-type Ca2+ channels in nociception
and our recent in vivo and in vitro studies
focusing primarily on 5α-
and 5β-reduced
neuroactive steroids and redox agents that are potent modulators
of neuronal T-type Ca2+ channels.
[Back to top]
Density is Density – On the Relation Between
Quantity of T-Type Ca2+
Channels and Neuronal Electrical Behavior
E. Chorev, Y. Manor and Y. Yarom
The electroresponsiveness fingerprint of a neuron reflects
the types and distributions of the ionic channels that are
embedded in the neuronal membrane as well as its morphology.
Theoretical analysis shows that subtle changes in the density
of channels can contribute substantially to the electroresponsive
fingerprints of neurons. We have confirmed these predictions,
using the dynamic clamp approach to emulate changes in channels'
densities in neurons from the inferior olive. We demonstrate
how the density of T-type channels determines the behavioral
destiny of neurons. We argue that regulation of channel densities
could be an efficient mechanism for controlling the electrical
activity of single cells, as well as the output of neuronal
networks.
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