Page 384 - Basic _ Clinical Pharmacology ( PDFDrive )

370 SECTION V Drugs That Act in the Central Nervous System

Natural Toxins: Tools For Characterizing TABLE 21–1 Some toxins used to characterize ion
channels.
Ion Channels
Channel Types Mode of Toxin Action Source
Evolution is tireless in the development of natural toxins. Voltage-gated
A vast number of variations are possible with even a small Sodium channels
number of amino acids in peptides, and peptides make up
only one of a broad array of toxic compounds. For example, Tetrodotoxin (TTX) Blocks channel from Puffer fish
outside
the predatory marine snail genus Conus includes over 3000
different species. Each species kills or paralyzes its prey with Batrachotoxin (BTX) Slows inactivation, shifts Colombian
frog
activation
a venom that contains 50–200 different peptides or proteins. Potassium channels
Furthermore, there is little duplication of peptides among
Conus species. Other animals with useful toxins include Apamin Blocks “small Honeybee
Ca-activated” K channel
snakes, frogs, spiders, bees, wasps, and scorpions. Plant spe-
cies with toxic (or therapeutic) substances are referred to in Charybdotoxin Blocks “big Ca-activated” Scorpion
K channel
several other chapters of this book.
Since many toxins act on ion channels, they provide a Calcium channels
wealth of chemical tools for studying the function of these Omega conotoxin Blocks N-type channel Pacific cone
channels. In fact, much of our current understanding of the (ω-CTX-GVIA) snail
properties of ion channels comes from studies utilizing only Agatoxin (ω-AGAIVA) Blocks P-type channel Funnel web
spider
a small percentage of the highly potent and selective toxins
that are now available. The toxins typically target voltage- Ligand-gated
sensitive ion channels, but a number of very useful toxins Nicotinic ACh receptor
block ligand-gated ion channels receptors. Table 21–1 lists α-Bungarotoxin Irreversible antagonist Marine snake
some of the toxins most commonly used in research, their GABA A receptor
mode of action, and their source. Picrotoxin Blocks channel South Pacific
plant
Glycine receptor
Strychnine Competitive antagonist Indian plant
Neurotransmitters exert their effects on neurons by binding
to two distinct classes of receptor. The first class is referred to as AMPA receptor
ligand-gated channels, or ionotropic receptors. These receptors Philanthotoxin Blocks channel Wasp
consist of multiple subunits, and binding of the neurotransmitter
ligand directly opens the channel, which is an integral part of the
receptor complex (see Figure 22–6). These channels are insensi- function. This mechanism accounts for the inhibition of neu-
tive or only weakly sensitive to membrane potential. Activation rotransmitter release that occurs when presynaptic metabotropic
of these channels typically results in a brief (a few milliseconds receptors are activated. In contrast, when these receptors are post-
to tens of milliseconds) opening of the channel. Ligand-gated synaptic, they activate (cause the opening of) potassium channels,
channels are responsible for fast synaptic transmission typical of resulting in a slow postsynaptic inhibition. Metabotropic recep-
hierarchical pathways in the CNS (see following text). tors can also modulate voltage-gated channels less directly by the
The second class of neurotransmitter receptor is referred to generation of diffusible second messengers (Figure 21–2E). A
as metabotropic receptors (Figure 21–2C). These are seven- classic example of this type of action is provided by the β adre-
transmembrane G protein-coupled receptors of the type described noceptor, which generates cAMP via the activation of adenylyl
in Chapter 2. The binding of neurotransmitter to this type of cyclase (see Chapter 2). Whereas membrane-delimited actions
receptor does not result in the direct gating of a channel. Rather, occur within microdomains in the membrane, second messenger-
binding to the receptor engages a G protein, which results in the mediated effects can occur over considerable distances. Finally, an
production of second messengers that mediate intracellular signal- important consequence of the involvement of G proteins in recep-
ing cascades such as those described in Chapter 2. tor signaling is that, in contrast to the brief effect of ionotropic
In neurons, activation of metabotropic neurotransmitter recep- receptors, the effects of metabotropic receptor activation can last
tors often leads to the modulation of voltage-gated channels. tens of seconds to minutes. Metabotropic receptors predominate
These interactions can occur entirely within the plane of the in the diffuse neuronal systems in the CNS (see below).
membrane and are referred to as membrane-delimited pathways
(Figure 21–2D). In this case, the G protein (often the βγ subunit) THE SYNAPSE & SYNAPTIC POTENTIALS
interacts directly with a voltage-gated ion channel. In general, two
types of voltage-gated ion channels are the targets of this type The communication between neurons in the CNS occurs through
of signaling: calcium channels and potassium channels. When chemical synapses in the majority of cases. (A few instances of
G proteins interact with calcium channels, they inhibit channel electrical coupling between neurons have been documented,