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.
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