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

372
SECTION II
NEUROPHARMACOLOGY
selectively increasing permeability to Cl − . Responses to
receptors with a channel as part of its structure tends to
be rapid since the effects are direct and generally do not
require multiple steps or a series of protein- protein interactions
leading to enzyme activation. Oligomeric ion
channel receptors are composed of multiple subunits,
each usually having six transmembrane domains
(Figure 14–2). Ion channel receptors for neurotransmitters
contain sites for reversible modulation by protein
kinases and phosphoprotein phosphatases and sequences
responsible for voltage- gating. Receptors with this structure
include nicotinic cholinergic receptors; the receptors
for the amino acids GABA, glycine, glutamate, and
aspartate; and the 5-HT 3
receptor (Figure 14–5A).
The second major group of receptors is the
G- protein coupled receptors (GPCRs), which interact
with heterotrimeric GTP- binding proteins (Chapter 3).
GPCRs are heptaspanning membrane proteins with an
extracellular amino terminus and an intracellular carboxy
terminus (Figures 14–5B and 14–6). Comparison
+
H S R N P A L L F A S G N G P Q G M NH
A
3
P
D
V L V I A C A L L C V I V M L I I M V F T G M I P L I Y
T A I S T I A V D I V R V Y S I G L C R S 330
A Y N T R Y F A A K N K R V F Q T K A
P I E C
TM1 F
L 270
Intracellular
T
K K
R
K
A
H E
D A Q L L
V TM3 I
E
K
F
L R
60
F
F T
T
L R Q L Q L C F K S
E Q
R
K
S
PKA
R L
S
L TM5 I TM6
140
R
S
P
S
D
R
F Q
K PKA
S
K Y
L
i 1
Q
E S
L
G
i R
K
2 i 3
H
F
A
240
G
H
T
350 Y
V N
V Q D
Q L S Q E G R
G
H
D
e 2
V
T
N C Y A E
Q
E
Q
I
T
R
e 1 A
C 190
D
100
E
C
E 30
T F
Q
D
e 3
V
W
G
N
H
F
300
W
M
F
T
F
N L
V
K
W
A
T
D I
R
V
M TM2 C
R TM4 N
Q
K TM7
Extracellular
G M G L I H E F W Y W H Q A Y I V H E V Y
I V M S A A G F T S I D M Q I P A I A S V I N V I L L N
L I V P V V V L C L F S S I V I F F W I G
L A I V A L G M V T A S T L G S S F V V P L W C Y V N S
F G N V L D I E T V I W P L V L T F G F N
N
G
Y
E Q E V H Y G S Q E G T N G N S S
K
E
N
K L L C E D L P G T E D F V G H 390
Q
– OOC L L S D N T S C N R G Q S D I N D S P V
G
T
Figure 14–6. The β adrenergic receptor (βAR). This two- dimensional bead- on- a string model illustrates features common to most heptaspanning
GPCRs. Red lines mark 10-amino acid regions. The amino terminus (N) is extracellular and the carboxyl terminus (C) is
intracellular; in between are 7 hydrophobic transmembrane (TM) domains and alternating intracellular and extracellular loops (e 1-3
and i 1-3
). Glycosylation sites are found near the N terminus; consensus sites for phophorylation by PKA (arrows) are found in the i 3
loop and the carboxy terminal tail. Multiple sites for βARK occur throughout the carboxy terminal region. An aspartate residue in TM 3
(asp113) interacts with the nitrogen of catecholamine agonists while two serines (ser204, ser207) in TM 5
interact with the hydroxyl
groups on the phenyl ring of catecholamine agonists. A cysteine residue (cys 341) is a substrate for palmitoylation. Interaction of the
palmitoyl group with membrane lipids reduces the flexibility of the carboxy tail. (Reprinted by permission from Macmillan Publishers
Ltd: Rasmussen SGF, Choi H-J, Rosenbaum DM et al: Crystal structure of the human β2 adrenergic G-protein-coupled receptor.
Nature 450:383, 2007. Copyright © 2007.)