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

A
GABA and
glycine receptors
C
N
B
CLC Cl – channels
M4
C
CFTR
369
M1 M2 M3
M4
M1 M2 M3
M5
M6 M7
M8
M9–M12
M1 M2 M3
M4
M5 M6
M7
M8 M9
M10
M11 M12
N
M13
C
N
NBF1
R
C
NBF2
Figure 14–3. Structure models of three families of Cl − channel. A. The γ- aminobutyric acid (GABA) and glycine receptor channels.
B. CLC Cl − channel. C. CFTR (cystic fibrosis transmembrane condiuctance regulator) channel. (M, transmembrane domains; NBF,
nucleotide- binding fold; R, regulatory [phosphorylation] domain.) (Reproduced with permission from Jentsch J. Chloride channels:
A molecular perspective. Curr Opin Neurobiol, 1996, 6:303–310. Copyright © Elsevier.)
CHAPTER 14
repeats of a putative six- transmembrane domain (Figure
14–2), while the K + channel family contains greater
molecular diversity. One structural form of voltageregulated
K + channels consists of subunits composed
of a single putative six- transmembrane domain. The
inward rectifier K + channel structure, in contrast, has
two membrane- spanning domains, retaining a general
configuration corresponding to transmembrane spans 5
and 6 of voltage- dependent channels with the interposed
“pore region” that penetrates only the exofacial
surface membrane (Figure 14–2). Within the CNS, variants
of the K + channels (the delayed rectifier, the Ca 2+ -
activated K + channel, and the after- hyperpolarizing K +
channel) regulated by intracellular second messengers
have been shown to underlie complex forms of synaptic
modulation (Greengard, 2001).
Ligand- gated ion channels, regulated by the binding
of neurotransmitters, form a distinct group of ion
channels (Figure 14–4). The structurally defined channel
molecules can be examined to determine how drugs,
toxins, and imposed voltages alter neuronal excitability.
Ca 2+ is an important signaling molecule present
at a concentration of 1.25 mM in extracellular fluid and
at very low concentrations (~100 nM) intracellularly in
resting cells, rising to 1 μM upon excitation. Multiple
classes of Ca 2+ channel exist (Yu et al., 2005). Like Na +
channels, Ca 2+ channels have a principal subunit called
an α1 subunit as well as three or four additional subunits.
The α1 subunit includes the conduction pore,
voltage sensor, and gating apparatus as well as sites for
channel regulation by drugs. They are structurally similar
to the α-subunit of Na + channels (Figure 14–2). A
channel- mediated influx of Ca 2+ can lead to muscle
contraction, transmitter release, and alterations in gene
expression. Ca 2+ channels were originally classified
according to electrophysical properties (Table 14–1).
L-type Ca 2+ channels are activated by large depolarization
and can remain open for 500 milliseconds or
longer. In contrast, T- type channels are activated by
small depolarization and since they are subject to voltage
dependent inactivation, they are open only transiently.
A
B
Exterior
Interior
L
L
L
L
L
TM2
Hydrophobic
ring
Figure 14–4. Predicted 3- D structure of a ligand-gated ion channel
receptor in a postsynaptic membrane. A. These channels consist of
a cylindrical membrane- embedded structure with a central pore. The
second transmembrane domain (TM2) of each subunit lines the pore
and bends inward to block ion flow through the channel. B.A highly
conserved leucine residue (L) in the TM2 bend of each subunit is
believed to protrude into the pore to form a tight hydrophobic ring,
which may act as a barrier to the flow of hydrated ions across the
channel. (Redrawn with permission from Nestler EJ, Hyman SE,
Malenka RC (eds). Molecular Neuropharmacology. New York:
McGraw-Hill, 2000, p 174. Copyright © 2009 by The McGraw-
Hill Companies, Inc. All rights reserved.)
NEUROTRANSMISSION AND THE CENTRAL NERVOUS SYSTEM