DƯỢC LÍ Goodman & Gilman's The Pharmacological Basis of Therapeutics 12th, 2010

60 voltage-gated (Jegla et al., 2009). The voltage-gated K v
channels
form channels as tetramers with topology similar to the Na+ and
Ca 2+ channels, but rather than having four domains, they consist of
four separate subunits that each incorporate six membrane-spanning
domains. The inwardly rectifying K + channel subunits only contain
two membrane-spanning domains surrounding the pore. In each of
these cases, the native channel is a tetramer formed from four individual
subunits. A final group of K + channels is the tandem or twopore
domain “leak” K + channels; each subunit in this group has four
membrane-spanning domains surrounding two P loops, and these
form channels as dimers. The inwardly rectifying channels and the
two-pore channels are voltage insensitive and are regulated by
G proteins and H + ions and are greatly stimulated by general anesthetics.
All these channels are expressed in nerve, cardiac tissue,
skeletal and smooth muscle, as well as non-excitable tissues.
Increasing K + conductance through these channels drives the membrane
potential more negative; thus, these channels are important in
regulating resting membrane potential and resetting the resting membrane
at −70 to −90 mV following depolarizaion. Some forms of
epilepsy are caused by natural mutations in K v
channels, and drugs
such as retigabine that favor opening of K v
channels are under study
for the treatment of epilepsy (Rogawski and Bazil, 2008). The cardiac
KCNH2 channel, known as hERG (human ether-a-go-go-related
gene), is responsible for hereditary as well as acquired (druginduced)
long QT syndrome. It is also the primary target of many
anti-arrhythmic drugs that prolong repolarization.
SECTION I
GENERAL PRINCIPLES
Ligand-Gated Channels. Channels activated by the binding
of a ligand to a specific site in the channel protein
have a diverse architecture and set of ligands. Major ligand-gated
channels in the nervous system are those that
respond to excitatory neurotransmitters such as acetylcholine
or glutamate (or agonists such as AMPA and
NMDA) and inhibitory neurotransmitters such as
glycine or γ-aminobutyric acid (GABA) (Purves and
McNamara, 2008). Activation of these channels is
responsible for the majority of synaptic transmission by
neurons both in the CNS and in the periphery (Chapters
8, 11, and 14). In addition, there are a variety of more
specialized ion channels that are activated by intracellular
small molecules, and are structurally distinct from
conventional ligand-gated ion channels. These include
ion channels that are formally members of the K v
family,
such as the hyperpolarization and cAMP-gated
(HCN) channel expressed in the heart (Wahl-Schott and
Biel, 2009) that is responsible for the slow depolarization
seen in phase 4 of AV and SA nodal cell action
potentials (Chapter 29), and the cyclic nucleotide-gated
(CNG) channels important for vision (Chapter 64). The
intracellular small molecule category of ion channels
also includes the IP 3
-sensitive Ca 2+ channel responsible
for release of Ca 2+ from the ER and the sulfonylurea
“receptor” (SUR1) that associates with the K ir
6.2 channel
to regulate the ATP-dependent K + channel (K ATP
) in
pancreatic beta cells. The K ATP
channel is the target of
oral hypoglycemic drugs such as sulfonylureas and
meglitinides that stimulate insulin release from pancreatic
β cells and are used to treat type 2 diabetes (Chapter
43). Other specialized channels include the 5-HT 3
-
regulated channel expressed on afferent vagal nerves
that stimulates emesis. Ondansetron is an important
antagonist of the 5-HT 3
-gated channel used to inhibit
emesis caused by drugs or disease (Chapter 46).
The nicotinic acetylcholine receptor provides an instructive
example of a ligand-gated ion channel. Isoforms of this channel are
expressed in the CNS, autonomic ganglia and at the neuromuscular
junction (Figure 3–9B). The pentameric channel consists of four different
subunits (2α, β, δ, γ) in the neuromuscular junction or two different
subunits (2α, 3β) in autonomic ganglia (Purves and
McNamara, 2008). Each α subunit has an identical acetylcholine
binding site; the different compositions of the other three subunits
between the neuronal and neuromuscular junction receptors accounts
for the ability of competitive antagonists such as rocuronium to
inhibit the receptor in the neuromuscular junction without effect on
the ganglionic receptor. This property is exploited to provide muscle
relaxation during surgery with minimal autonomic side effects
(Chapter 11). Each subunit of the receptor contains a large, extracellular
N-terminal domain, four membrane-spanning helices (one of
which lines the pore in the assembled complex), and an internal loop
between helices 3 and 4 that forms the intracellular domain of the
channel. The pore opening in the channel measures ~3 nm whereas
the diameter of a Na + or K + ion is only 0.3 nm or less. Accordingly,
ligand-gated ion channels do not possess the exquisite ion selectivity
found in most voltage-activated channels and activation of the nicotinic
acetylcholine receptor allows passage of both Na + and K + ions.
The major excitatory transmitter at CNS synapses is glutamate.
There are three types of ionotropic glutamate receptors
(AMPA, NMDA, and kainate), named after the ligands that selectively
activate them. They have a topology similar to that of the nicotinic
acetylcholine receptor: the channel is made up of five subunits
organized with a large extracellular region, a pore, and a small intracellular
face. Activation of these channels with glutamate markedly
increases Na + and K + conductance leading to depolarization. NMDA
receptors are less ion-selective; activation increases Na + , K + , and
Ca 2+ conductance, with the Ca 2+ signal being used for additional signaling
events.
Over one-third of synapses in the brain are inhibitory; the
major inhibitory transmitters are glycine and γ-aminobutyric acid
(GABA). Glycine and ionotropic GABA A
receptors have a topology
like that of the glutamate and nicotinic acetylcholine receptors, with
five subunits (α, β, γ, δ and ρ), a ligand-binding domain, and poreforming
helices. Activation of these channels increases Cl − conductance,
which hyperpolarizes the cell membrane and inhibits
excitability (Purves and McNamara, 2008). GABA A
receptors are
targets of important sedative-hypnotic drugs such as the benzodiazepines
and barbituates, and are also important in the mechanisms
of ethanol and general anesthetics (Chapters 17, 19, and 23).
TRP Channels. The transient receptor potential (TRP)
channels comprise a superfamily of ubiquitously