| Current
Pharmaceutical Design
ISSN: 1381-6128
Current Pharmaceutical Design
Volume 12, Number 28, 2006
Contents
Membrane Channels as Therapeutic Targets
Executive Editor: Jean-Claude Hervé
Editorial Pp. 3571-3572
Muscarinic Acetylcholine Receptors Pp. 3573-3581
M. Ishii and Y. Kurachi
[Abstract]
Pharmacological Intervention at Ionotropic Glutamate
Receptor Complexes Pp. 3583-3596
R. Planells-Cases, J. Lerma and A. Ferrer-Montiel
[Abstract]
The Pharmacology of Cyclic Nucleotide-Gated Channels:
Emerging from the Darkness Pp. 3597-3613
R.L. Brown, T. Strassmaier, J.D. Brady and J.W. Karpen
[Abstract]
5-HT3 Receptors Pp. 3615-3630
A.J. Thompson and S.C.R. Lummis
[Abstract]
Molecular Mechanisms of Cardiac Voltage-Gated
Potassium Channelopathies Pp. 3631-3644
G.W. Abbott
[Abstract]
Mechanosensitive Channels: Therapeutic Targets
in the Myocardium? Pp. 3645-3663
E. White
[Abstract]
Anaesthetic Drugs: Linking Molecular Actions to
Clinical Effects Pp. 3665-3679
C. Grasshoff, B. Drexler, U. Rudolph and B. Antkowiak
[Abstract]
Voltage-Gated Sodium Channels: New Targets in
Cancer Therapy? Pp. 3681-3695
S. Roger, M. Potier, C. Vandier, P. Besson and J.-Y. Le
Guennec
[Abstract]
Abstracts
[Back
to top]
Editorial
Membrane Channels as Therapeutic Targets
The production of new molecular entities endowed with salutary
medicinal properties is a formidable challenge that involve
several steps and requests rational target identification,
recognition and avoidance of adverse properties of therapeutics
before commitment to clinical trials, monitoring of clinical
efficacy using surrogate markers and individualized approaches
to disease treatment. The first to face up to is the initial
identification and selection of macromolecular targets upon
which de novo drug discovery programs can be initiated. A
drug target needs to answer several criteria (as known biological
function(s), robust assay systems for in vitro characterisation
and high-throughput screening) and to be specifically modified
by and accessible to small molecular weight compounds in vivo.
Membrane channels have many of these attributes and can be
viewed as suitable targets for small molecule drugs.
Membrane channels are allosteric proteins that open and close
a permeable pore (a process called gating), allowing ions
and sometimes small molecules to flow across the cell membrane
in a regulated manner. Their gating can be regulated by various
stimuli including changes in membrane voltage, binding of
extracellular or intracellular ligands, membrane stretch,
enzymes and G-proteins. They play critical roles in a broad
range of physiological processes, including electrical signal
transduction, chemical signalling (involving different second
messengers), transepithelial transport, regulation of cytoplasmic
or vesicular ion concentration and pH, as well as regulation
of cell volume. Channel dysfunction may lead to a number of
diseases termed channelopathies, and a number of common diseases
(e.g. epilepsy, hypertension, arrhythmia, chronic
pain or type II diabetes) are primarily treated by drugs that
modulate ion channel activities.
The cell-based methods for evaluating membrane channel pharmacology
are based on several distinct techniques such as electrophysiology,
fluorescence, radioligand binding or displacement, and radiotracer
flux assays. A better understanding of membrane channel structures
and of channel functions has been achieved in recent years
by three main scientific advances, the patch-clamp technique,
the use of selective neurotoxins and the cloning and sequencing
of genes. They allowed to investigate the pharmacological
effects of traditional (antiarrhythmic, antiepileptic, ...)
drugs and the development of new approaches. This issue of
Current Pharmaceutical Design, the third of four parts, for
which I have the honour to be Executive Guest Editor, addresses
topical issues to some of these channels.
A wide range of neurotransmitters, polypeptides and inflammatory
mediators transduce their signals into the interior of cells
by specific interactions with cell-surface receptors that
are coupled to G-protein. Muscarinic acetylcholine receptors,
one of the most familiar of them, mediate transmission of
acetylcholine to neuronal or effector cells. There are five
subtypes of closely homologous muscarinic receptors which
are coupled by means of heterotrimeric G-proteins to a variety
of signalling pathways resulting in a multitude of target
cell effects. Masaru Ishii and Yoshihisa Kurachi [1] review
the latest advances in the structural and functional characterization
of these receptors and the pharmaceutical development of muscarinic
receptor ligands.
Glutamate is regarded as the most widespread excitatory neurotransmitter
in the mammalian brain. Two classes of glutamate receptors
have been cloned, the ionotropic (ligand-gated ion channels)
and the metabotropic (G protein-coupled receptors). Ionotropic
glutamate receptors mediate basic information processing in
the brain and induce changes in synaptic efficacy, but their
functional realm has been found to extend well outside the
central nervous system to include roles in insulin secretion,
bone resorption, cardiac pacemaking, as well as involvement
in taste and tactile sensation. Rosa Planells-Cases, Juan
Lerma and Antonio Ferrer-Montiel [2] overview the current
knowledge available concerning the pharmacology of these channels.
Cyclic nucleotide-gated ion channels are non-selective cation
channels that are opened by the direct binding of intracellular
cyclic nucleotides and behave as molecular amplifiers, with
large changes in activity resulting from small changes in
cyclic nucleotide concentration. Taking advantage of emerging
structural information and the increasing knowledge of the
biophysical properties of these channels, some promising compounds
and strategies have begun to emerge. Lane Brown, Timothy Strassmaier,
James Brady and Jeffrey Karpen [3] discuss progress on two
fronts, cyclic nucleotide analogues as both activators and
competitive inhibitors, and inhibitors that target the pore
or gating machinery of the channel.
Serotonin receptors are highly heterogeneous and they have
been regrouped within seven different families (5-HT1 to 5-HT7).
All of them are G-protein coupled receptors with each family
sharing structural, pharmacological and transductional characteristics,
except 5-HT3 which is a ligand-gated ion channel. Andrew Thompson
and Sarah Lummis [4] show how structure-function studies have
provided us with a detailed image of the 5-HT3 pharmacophore
and discuss the current and future therapeutic potential of
compounds that act via this receptor.
Voltage-gated potassium (Kv) channels mediate rapid, selective
diffusion of K+ ions through the plasma membrane,
controlling cell excitability, secretion and signal transduction.
In cardiac myocytes, the particular duration and morphology
of the action potential, largely a product of precisely-timed
gating and the current density of the specific Kv channels
expressed, are essential for a regular heart-beat. Specific
Kv channel expression, and thus action potential duration
and morphology, differ between myocytes from different regions
of the heart, and this offers hope for the development of
Kv channel isoform-specific drugs to treat specific cardiac
rhythm disturbances, as summarised by Geoffrey Abbott [5].
Cells can respond to a variety of mechanical stimuli such
as tension, pressure, and shear stress. As membrane channels
gated by mechanical stimuli (mechanosensitive channels, MSCs)
are implicated in many normal and pathological cellular responses,
they present a valid target for therapeutic agents. However
the process of mechanotranduction, the structure, function
and pharmacology of eukaryotic MSCs are not well understood
and matching experimental and in vivo stimuli is
difficult. Edward White [6] presents an overview of MSCs and
of factors involved in their regulation, with a focus on the
field of cardiology. He more particularly examines the role
of MSCs in the generation of stretch-activated arrhythmias
and the potential for treating arrhythmias by targeting these
channels.
Despite over 150 years of clinical use, the mechanisms of
action of general anaesthetics have remained unknown until
recently. For a long time, attention focussed on their hydrophobic
nature and on their potential effects on the bulk physical
properties of cell membranes, leading to the widespread acceptance
of the ‘nonspecific’ nature of general aesthetic
action. It now appears that different molecular targets in
various regions of the nervous system, summarised by Christian
Grasshoff, Berthold Drexler, Uwe Rudolph and Bernd Antkowiak
[7], are involved in the multiple components of anaesthetic
action, and that these targets can vary between specific anaesthetics.
The early detection and treatment of cancers have increased
survival and improved clinical outcomes. The development of
metastases is often associated with a poor prognostic of survival.
Finding early markers of metastasis and developing new therapies
against their development is a great challenge. For a few
years, there is more evidence that ionic channels are involved
in the oncogenic process. Among these, voltage-gated sodium
channels expressed in non-nervous or non-muscular organs are
often associated with the metastatic behaviour of different
cancers. Sébastien Roger, Marie Potier, Christophe
Vandier, Pierre Besson and Jean-Yves Le Guennec overview the
current knowledge on the functional expression of voltage-gated
sodium channels and their biological roles in different cancers.
I wish to thank all the authors and co-authors for their commitments
and the anonymous reviewers who contributed by their constructive
remarks to the excellence of this issue.
References
[1] Ishii M, Kurachi Y. Muscarinic acetylcholine receptors.
Curr Pharm Des 2006; 12(28): 3573-3581.
[2] Planells-Cases R, Lerma J, Ferrer-Montiel A. Pharmacological
intervention at ionotropic glutamate receptor complexes. Curr
Pharm Des 2006; 12(28): 3583-3596.
[3] Brown RL, Strassmaier T, Brady JD, Karpen JW. The Pharmacology
of Cyclic Nucleotide-Gated Channels: Emerging from the Darkness.
Curr Pharm Des 2006; 12(28): 3597-3613.
[4] Thompson AJ, Lummis SCR. 5-HT3 receptors. Curr Pharm Des
2006; 12(28): 3615-3630.
[5] Abbott GW. Molecular mechanisms of cardiac voltage-gated
potassium channelopathies. Curr Pharm Des 2006; 12(28): 3631-3644.
[6] White E. On the Mechanosensitive channels: therapeutic
targets in the myocardium ? Curr Pharm Des 2006; 12(28): 3645-3663.
[7] Grasshoff C, Drexler B, Rudolph U, Antkowiak B. Anaesthetic
drugs: Linking molecular actions to clinical effects. Curr
Pharm Des 2006; 12(28): 3665-3679.
[8] Roger S, Potier M, Vandier C, Besson P, Le Guennec JY.
Voltage-gated sodium channels: new targets in cancer therapy?
Curr Pharm Des 2006; 12(28): 3681-3695.
Jean-Claude Hervé
Interactions et Communications Cellulaires
UMR CNRS 6187, PBS, 40 avenue du R. Pineau
86022 POITIERS Cédex
France
[Back to top]
Muscarinic Acetylcholine Receptors
M. Ishii and Y. Kurachi
Muscarinic acetylcholine receptors mediate diverse physiological
functions. At present, five receptor subtypes (M1
- M5) have been identified. The odd-numbered receptors
(M1, M3, and M5) are preferentially
coupled to Gq/11 and activate phospholipase C,
which initiates the phosphatidylinositol trisphosphate cascade
leading to intracellular Ca
2+ mobilization and activation of protein kinase
C. On the other hand, the even-numbered receptors (M2
and M4) are coupled to Gi/o, and inhibit
adenylyl cyclase activity. They also activate G protein-gated
potassium channels, which leads to hyperpolarization of the
plasma membrane in different excitable cells. Individual members
of the family are expressed in an overlapping fashion in various
tissues and cell types. Recent gene targeting approaches have
unraveled the specific function of these muscarinic receptor
subtypes, which were not able to be fully elucidated with
pharmacological approaches because of the non-selective effects
of the available ligands. Based on these findings, muscarinic
receptors have been emerging as an important therapeutic target
for various diseases, including dry mouth, incontinence and
chronic obstructive pulmonary disease. Here we review the
latest advances in the structural and functional characterization
of muscarinic acetylcholine receptors and the pharmaceutical
development of muscarinic receptor ligands.
[Back to top]
Pharmacological Intervention at Ionotropic Glutamate
Receptor Complexes
R. Planells-Cases, J. Lerma and A. Ferrer-Montiel
L-glutamate is considered the main excitatory neurotransmitter
in the mammalian brain. Paradoxically, L-glutamate is also
the most important excitotoxin pivotally involved in the aetiology
of several neurodegenerative diseases such as stroke, Alzheimer,
Parkinson, amyotropic lateral sclerosis, Huntington and neuropathic
pain. L-glutamate signalling is transduced both presynaptically
and postsynaptically by metabotropic and ionotropic receptors.
Three types of glutamate-gated channels integrate the synaptic
signal, namely AMPA, kainate and NMDA receptors. Sustained
activation of these receptors, and especially of the NMDA
receptor, is a casuistic phenomenon that leads to the neuronal
death underlying neurodegeneration. Thus, pharmacological
intervention at these neuronal receptors and their synaptic
protein complexes is a valuable therapeutic strategy. The
approval of memantine, a safe, well-tolerated uncompetitive
NMDA antagonist for the treatment of moderate to severe Alzheimer
dementia validates ionotropic glutamate receptors as key therapeutic
targets of neurodegenerative diseases in humans. As a consequence,
an enormous effort is being carried out to identify and develop
safe and potent antagonists for the clinics. In this review,
we will describe progress in this important arena of human
health.
[Back to top]
The Pharmacology of Cyclic Nucleotide-Gated Channels:
Emerging from the Darkness
R.L. Brown, T. Strassmaier, J.D. Brady and J.W. Karpen
Cyclic nucleotide-gated (CNG) ion channels play a central
role in vision and olfaction, generating the electrical responses
to light in photoreceptors and to odorants in olfactory receptors.
These channels have been detected in many other tissues where
their functions are largely unclear. The use of gene knockouts
and other methods have yielded some information, but there
is a pressing need for potent and specific pharmacological
agents directed at CNG channels. To date there has been very
little systematic effort in this direction - most of what
can be termed CNG channel pharmacology arose from testing
reagents known to target protein kinases or other ion channels,
or by accident when researchers were investigating other intracellular
pathways that may regulate the activity of CNG channels. Predictably,
these studies have not produced selective agents. However,
taking advantage of emerging structural information and the
increasing knowledge of the biophysical properties of these
channels, some promising compounds and strategies have begun
to emerge. In this review we discuss progress on two fronts,
cyclic nucleotide analogs as both activators and competitive
inhibitors, and inhibitors that target the pore or gating
machinery of the channel. We also discuss the potential of
these compounds for treating certain forms of retinal degeneration.
[Back to top]
5-HT3 Receptors
A.J. Thompson and S.C.R. Lummis
The 5-HT3 receptor is a member of the Cys-loop
family of ligand-gated ion channels. These receptors are located
in both the peripheral and central nervous systems, where
functional receptors are constructed from five subunits. These
subunits may be the same (homopentameric 5-HT3A
receptors) or different (heteropentameric receptors, usually
comprising of 5-HT3A and 5-HT3B receptor
subunits), with the latter having a number of distinct properties.
The 5-HT3 receptor binding site is comprised of
six loops from two adjacent subunits, and critical ligand
binding amino acids in these loops have been largely identified.
There are a range of selective agonists and antagonists for
these receptors and the pharmacophore is reasonably well understood.
There are also a wide range of compounds that can modulate
receptor activity. Studies have suggested many diverse potential
disease targets that might be amenable to alleviation by 5-HT3
receptor selective compounds but to date only two applications
have been fully realised in the clinic: the treatment of emesis
and irritable-bowel syndrome.
[Back to top]
Molecular Mechanisms of Cardiac Voltage-Gated Potassium
Channelopathies
G.W. Abbott
Potassium channels form highly K+ ion-selective
pores in the plasma membrane of excitable cells. Voltage-gated
potassium (Kv) channels open in response to membrane depolarization
to allow rapid diffusion of K+ ions out of the
cell, thus repolarizing the cell to restore a negative resting
membrane potential. Inherited mutations in Kv channel genes
produce abnormal cellular repolarization and cause diseases
of excitable tissues. Small molecule interactions with Kv
channels can cause similar pathologies. During the last decade
of research into Kv channels and associated diseases - termed
‘channelopathies’ - we have begun to understand
Kv channel function and dysfunction at the molecular level.
In this review, the molecular mechanisms of Kv channelopathies
are discussed, with particular emphasis on the overlap between
inherited and acquired disease, and the drive towards novel
channel-targeted therapies.
[Back to top]
Mechanosensitive Channels: Therapeutic Targets
in the Myocardium?
E. White
Mechanosensitivity is a property common to many cell types.
Because channels gated by mechanical stimuli (mechanosensitive
channels, MSCs) are implicated in many normal and pathological
cellular responses, they present a valid target for therapeutic
agents. However the process of mechanotranduction, the structure,
function and pharmacology of eukaryotic MSCs are not well
understood and matching experimental and in vivo
stimuli is difficult. With respect to the pharmacology of
these channels, a further complication arises because agents
that modulate the activity of MSCs may not even bind to the
channel itself, but may cause their effects by changing the
properties of the tension-sensing lipid bilayer and/or cytoskeleton.
MSCs in the myocardium are discussed in the context of their
probable role in the generation of stretch-activated arrhythmias.
The actions of the three most prominent agents used to study
MSCs in the heart, the lanthanide gadolinium, the aminoglycosidic
antibiotic streptomycin, and a peptide toxin isolated from
tarantula venom, GsMTx-4, are compared. While all three can
prevent mechanically-induced cardiac arrhythmias in experimental
situations, only GsMTx-4 seems to have the potential as a
novel therapeutic agent for the targeting of arrhythmias provoked
by MSCs.
[Back to top]
Anaesthetic Drugs: Linking Molecular Actions to Clinical
Effects
C. Grasshoff, B. Drexler, U. Rudolph and B. Antkowiak
The use of general anaesthetics has facilitated great advantages
in surgery within the last 150 years. General anaesthesia
is composed of several components including analgesia, amnesia,
hypnosis and immobility. To achieve these components, general
anaesthetics have to act via multiple molecular targets
at different anatomical sites in the central nervous system.
Much of our current understanding of how anaesthetics work
has been obtained within the last few years on the basis of
genetic approaches, in particular knock-out or knock-in mice.
Anaesthetic drugs can be grouped into volatile and intravenous
anaesthetics according to their route of administration. Common
volatile anaesthetics induce immobility via molecular
targets in the spinal cord, including glycine receptors, GABAA
receptors, glutamate receptors, and TREK-1 potassium channels.
In contrast, intravenous anaesthetics cause immobility almost
exclusively via GABAA receptors harbouring
β3
subunits. Hypnosis is predominantly mediated by β3-subunit
containing GABAA receptors in the brain, whereas
β2
subunit containing receptors, which make up more than 50%
of all GABAA receptors in the central nervous system,
mediate sedation. At clinically relevant concentrations, ketamine
and nitrous oxide block NMDA receptors. Unlike all other anaesthetics
in clinical use they produce analgesia.
Not only desired actions of anaesthetics, but also undesired
side effects are linked to certain receptors. Respiratory
depression involves β3
containing GABAA receptors whereas hypothermia
is largely mediated by GABAA receptors containing
β2
subunits. These recent insights into the clinically desired
and undesired actions of anaesthetic agents provide new avenues
for the design of drugs with an improved side-effect profile.
Such agents would be especially beneficial for the treatment
of newborn children, elderly patients and patients undergoing
ambulatory surgery.
[Back to top]
Voltage-Gated Sodium Channels: New Targets in Cancer
Therapy?
S. Roger, M. Potier, C. Vandier, P. Besson and J.-Y. Le
Guennec
Early detection and treatment of cancers have increased
survival and improved clinical outcome. The development of
metastases is often associated with a poor prognostic of survival.
Finding early markers of metastasis and developing new therapies
against their development is a great challenge. Since a few
years, there is more evidence that ionic channels are involved
in the oncogenic process. Among these, voltage-gated sodium
channels expressed in non-nervous or non-muscular organs are
often associated with the metastatic behaviour of different
cancers. The aim of this review is to describe the current
knowledge on the functional expression of voltage-gated sodium
channels and their biological roles in different cancers such
as prostate, breast, lung (small cells and non-small cells)
and leukaemia. In the conclusion, we develop conceptual approaches
to understand how such channels can be involved in the metastatic
process and conclude that blockers targeted toward these channels
are promising new therapeutic solutions against metastatic
cancers.
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