Biomedical Engineering Reference
In-Depth Information
within family A are closely related to each other than to receptors in family B and C and the like.
This grouping also coincides with the way ligands binds to the receptors. Thus, as illustrated in
Figure 12.3, the endogenous signaling molecules generally bind to the transmembrane region of
family A receptors (e.g., acetylcholine, histamine, dopamine, serotonin, opioid, and cannabinoid
GPCRs, Chapters 16 through 19), to both the extracellular loops and amino-terminal domain of
family B receptors (e.g., glucagon and GLP-1 GPCRs) and exclusively to the extracellular amino-
terminal domain of family C receptors (e.g., glutamate and GABA GPCRs, Chapter 15).
The intracellular loops of GPCRs interact with G proteins. As illustrated in Figure 12.4, the
G proteins are trimeric consisting of G
α
, G
β
, and G
γ
subunits. Receptor activation will cause an
interaction of the receptor with the trimeric G
αβγ
-protein, catalyzing an exchange of GDP for GTP
in the G
α
subunit whereupon the G protein disassociate into activated G
α
and G
βγ
subunits. Both of
these will then activate effector molecules such as adenylate cyclase or ion channels (Figure 12.4).
16 G
α
, 5 G
β
, and 12 G
γ
subunits have been identii ed in humans and like the receptors they form
groups based on the amino acid homology and the effectors they interact with.
e.g.,
α
2
, 5-HT
1
, M
2/4
,
D
2-4
, GABA
B
, opioid,
mGluR2, 3, 4, 6,7, 8
Ca
2+
P/Q-,
N-type
(Ca
v
2.1-3)
GIRK
(Kir3.1-
Kir3.4)
Adenylyl
cyclase
+
-
-
G
i/o
βγ
α
i
βγ
βγ
AT P
+
βγ
cAMP
K
+
PLC-β,
PI-3-Kβ/γ
e.g.,
β
1
/β
2
-adrenergic,
D
1
/D
5
e.g.,
M
1
/M
3
mGluR1, 5
α
1
, 5-HT
2
Adenylyl
cyclase
+
G
s
α
s
α
q
α
11
G
q/11
G
12/13
α
12
α
13
Rho-
GEF
PLC-β
AT P
+
+
cAMP
RhoA
(GDP)
PIP
2
DAG
RhoA
(GTP)
IP
3
[Ca
2+
]
i
PKC
FIGURE 12.4
Principal G protein coupling pathways for a range of 7TM receptors discussed in further detail
in Chapters 15 through 19. Receptor activation will catalyze an exchange of GDP for GTP in the α-subunit,
which leads to activation and separation of the α- and βγ-subunits. Both of these will modulate downstream
effectors. α
1-2
and β
1-2
, adrenergic receptor subtypes; D
1-5
, dopamine receptor subtypes 1-5; GIRK, G protein-
regulated inward rectii er potassium channel; 5-HT
1,2
, serotonin receptor subtypes 1 and 2; M
1-5
, muscar-
inic acetylcholine receptor subtypes 1 to 5; mGluR1-8, metabotropic glutamate receptor subtypes 1 to 8;
PLC-β, phospholipase C-β; PI-3-K, phosphoinositide-3-kinase; PIP
2
, phosphatidylinositol 4,5-bisphosphate;
IP
3
, inositol 1,4,5-trisphosphate; DAG, diacylglycerol; PKC, protein kinase C; Rho-GEF, Rho-guanine nucle-
otide exchange factor. (Adapted from Wettschreck, N. and Offermanns, S.,
Physiol. Rev
., 85, 1159, 2005. With
permission.)
