Biomedical Engineering Reference
In-Depth Information
Trp
84
Trp
84
Phe
330
Phe
330
O
Glu
199
Glu
199
O
-
N
+
N
+
His
440
His
440
O
His
440
O
O
O
Ser
200
Ser
200
N
O
H
+
HN
NH
NH
Ser
200
H
N
NH
O
N
+
HO
OH
H
H
His
440
His
440
OH
O
His
440
O
O
O
Ser
200
Ser
200
Ser
200
+
HN
N
NH
NH
N
NH
O
O
O
(A)
Trp
84
Phe
330
O
Glu
199
R
R
R
His
440
ON
His
440
O
Ser
200
N
O
H
Ser
200
NH
H
N
NH
O
R
HO
N
Slow
R
Trp
84
Phe
330
His
440
R
O
-
O
N
Glu
199
R
R
R
Ser
200
His
440
N
R
NH
N
O
OH
O
O
Ser
200
R
+
HN
NH
(B)
R
2
O
HL
R
2
P
O
R
2
P
O
O
-
Ser
200
O
R
1
PO
O
+
R
1
Ser
200
H
H
Ser
200
H
L
R
2
O
O
+
P
Ser
200
H
R=NO
(C)
R
1
FIGURE 16.7
Substrate catalysis of the AChE and inhibition of it. (A) Catalysis of ACh in the AChE.
(B) Inhibition of AChE by a reversible carbamoylating AChEI. (C) Formation of the phosphorus AChE
conjugate by organophosphorus AChEIs, and the following “aging” and oxime reactivation processes. R
1
,
O-alkyl or amid; R
2
, alkyl, O-alkyl or amid; L, leaving group.
16.4 MUSCARINIC ACh RECEPTORS
The mAChRs belong to family A of the superfamily of G-protein coupled receptors (GPCRs) (see
Chapter 12). Hence, the muscarinic component of cholinergic signaling is mediated by intracellular
second messenger cascades initiated by the coupling of the activated mAChRs to G-proteins and
other intracellular proteins such as b-arrestins. Five mAChR subtypes have been identii ed, termed
M
1
-M
5
. The M
1
, M
3
, and M
5
mAChRs are coupled to G
aq
-proteins and the resulting stimulation of
phospholipase C and intracellular release of Ca
2+
, whereas the M
2
and M
4
subtypes are coupled to
G
ao
and G
ai
proteins associated with inhibition of adenylate cyclase and a reduction of the intracel-
lular levels of cAMP.
The mAChRs are expressed abundantly in both the CNS and in the peripheral tissues. In recent
years, studies of “mAChR knock out mice,” where the expression of one of the i ve mAChR sub-
types have been eliminated have shed light on the functions of the respective mAChRs and the
therapeutic perspectives in selective targeting of these individual mAChRs.