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

706
AVP
AVP
V 2
β γ
α s
Adenylyl
Cyclase
Interstitial space
Basolateral membrane
functional water channels (aquaporin 2), their net shift
into apical membranes in response to V 2
-receptor
stimulation greatly increases water permeability of the
apical membrane (see Figures 25–20 and 25–21).
Degradation
ATP
cAMP
Principal cell
in collecting duct
PKA activity
1
A
2
P
N A
B
3
C
4
E
5 N A
P
6
SECTION III
MODULATION OF CARDIOVASCULAR FUNCTION
H 2 O
Multivesicular
Bodies (MVB)
Endocytosis
WCVs
–
Exocytosis
Apical membrane
WCVs = Water Channel Containing Vesicles
= Aquaporin-2 = Water Channel
Phosphorylated
Proteins
Figure 25–20. Mechanism of V 2
receptor-effector coupling.
Binding of vasopressin (AVP) to the V 2
receptor activates the
G S
-adenylyl cyclase-cAMP-PKA pathway and shifts the balance
of aquaporin 2 trafficking toward the apical membrane of the
principal cell of the collecting duct, thus enhancing water permeability.
Although phosphorylation of serine 256 of aquaporin 2 is
involved in V 2
receptor signaling, other proteins located both in
the water channel-containing vesicles and the apical membrane
of the cytoplasm also may be involved.
insertion of water channel-containing vesicles (WCVs)
into the apical membrane and a decreased rate of endocytosis
of WCVs from the apical membrane (Snyder
et al., 1992). Distribution of WCVs between the cytosolic
compartment and apical membrane compartment is thus
shifted in favor of the apical membrane compartment
(Nielsen et al., 1999). Because WCVs contain preformed
+
N
N
1
C
A
2
6
E
P
N N
N A
P
B
D
3
C
D
4
(4 monomers)
H 2 O
Figure 25–21. Structure of aquaporins. Aquaporins have six transmembrane
domains, and the NH 2
and COOH termini are intracellular.
Loops B and E each contain an asparagine-proline-alanine
(NPA) sequence. Aquaporins fold with transmembrane domains 1,
2, and 6 in close proximity and transmembrane domains 3, 4 and
5 in juxtaposition. The long B and E loops dip into the membrane,
and the NPA sequences align to create a pore through which water
can diffuse. Most likely aquaporins form a tetrameric oligomer.
At least seven aquaporins are expressed at distinct sites in the kidney.
Aquaporin 1, abundant in the proximal tubule and descending
thin limb, is essential for concentration of urine. Aquaporin 2,
exclusively expressed in the principal cells of the connecting
tubule and collecting duct, is the major vasopressin-regulated
water channel. Aquaporin 3 and aquaporin 4 are expressed in the
basolateral membranes of collecting-duct principal cells and provide
exit pathways for water reabsorbed apically by aquaporin 2.
Aquaporin 7 is in the apical brush border of the straight proximal
tubule. Aquaporins 6 to 8 are also expressed in kidney; their functions
remain to be clarified. Vasopressin regulates water permeability
of the collecting duct by influencing the trafficking of
aquaporin 2 from intracellular vesicles to the apical plasma membrane
(Figure 25–20). AVP-induced activation of the cAMP-PKA
pathway also enhances expression of aquaporin 2 mRNA and protein;
chronic dehydration thus causes up-regulation of aquaporin 2
and water transport in the collecting duct.
C