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

Dark
Light
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[Ca 2+ ]DK [cGMP]LT [Ca 2+ ]LT
[cGMP] DK
Ca 2+ Na + –
Ca 2+ /K +
Dark Light-activated
Na +
R T R*–T* Tα* P T*–P*
Na + –
Ca 2+ /K +
Na +
Ca 2+
GDP
GTP
cGMP
5’-GMP
Figure 64–8. Major steps in photoreceptor signaling. In dark-adapted rod photoreceptors (left side of diagram), cytoplasmic cyclic
GMP (green circles) and Ca 2+ concentrations are high, and some of the cyclic GMP–gated cation channels in the plasma membrane
(purple tetramer) are fully liganded and in the open state. Upon absorption of a photon by rhodopsin (R, red integral disk membrane
protein), isomerization of the 11-cis retinal chromophore occurs to activate the receptor (R*). This leads to binding of transducin (T,
pie-shaped heterotrimer) to R*, guanine nucleotide exchange of GDP (gray circle) for GTP (red circle), and formation of the activated
transducin subunit with bound GTP (T*). The T* species then binds phosphodiesterase 6 (PDE6) holoenzyme (P, blue catalytic
dimer with red subunits), causing de-inhibition by the subunit (T*-P*) and a large acceleration of catalysis of cyclic GMP
to 5-GMP at the active site (green arrow).The light-induced drop in cyclic GMP concentration (right side of diagram) causes the ligand-gated
ion channel to close, causing membrane hyperpolarization. Ongoing extrusion of calcium by the Na + –Ca 2+ /K + exchanger
in the absence of Ca 2+ influx through the channel also causes [Ca 2+ ] i
to decline, which is vital for the recovery process. DK, dark state;
LT, light-activated state. (Reproduced with permission from Zhang X, Cote RH. cGMP signaling in vertebrate retinal photoreceptor
cells. Front Biosci, 2005, 10:1191–1204.)
The visual cycle (Figure 64–8) is initiated by the absorption
of a photon of light, leading to the isomerization of 11-cisretinal
to the all-trans form covalently bound to rhodopsin, a G
protein–coupled receptor (GPCR). Activated rhodopsin interacts
with the heterotrimeric G protein transducin (G t
), initiating
GDP–GTP exchange and formation of the activated t
-GTP subunit.
t
-GTP binds to and activates a cyclic GMP phosphodiesterase,
PDE6, resulting in a rapid drop in the local concentration
of cyclic GMP. The decline in cyclic GMP permits dissociation
of cyclic GMP from open cyclic GMP–gated ion channels (open
in the dark), causing channel closure and hyperpolarization. This
is followed by a stimulation of GC (guanylyl cyclase) activity,
re-opening of the ion channel, and restoration of initial cellular
Ca 2+ . A series of reactions involving rhodopsin kinase, arrestin,
recoverin, and the GTPase activity of t
-GTP also help to restore
the system to the ground state, with re-formation of the heterotrimeric
form of G t
-GDP (Cote, 2007).
Vitamin A Deficiency and Vision. Humans deficient in vitamin A
lose their ability for dark adaptation. Rod vision is affected more
than cone vision. Upon depletion of retinol from liver and blood,
usually at plasma concentrations of retinol of <0.2 mg/L (0.70 μM),
the concentrations of retinol and rhodopsin in the retina fall. Unless
the deficiency is overcome, opsin, lacking the stabilizing effect of
retinal, decays, and anatomical deterioration of the rod outer segment
occurs. In rats maintained on a vitamin A–deficient diet, irreversible
ultrastructural changes leading to blindness then supervene,
a process that takes ~10 months.
Following short-term deprivation of vitamin A, dark adaptation
can be restored to normal by the addition of retinol to the diet.
However, vision does not return to normal for several weeks after
adequate amounts of retinol have been supplied. The reason for this
delay is unknown.
Vitamin A and Epithelial Structures. The functional and structural
integrity of epithelial cells throughout the body is dependent on an
adequate supply of vitamin A. The vitamin plays a major role in the
induction and control of epithelial differentiation in mucussecreting
or keratinizing tissues. In the presence of retinol or
retinoic acid, basal epithelial cells are stimulated to produce
mucus. Excessive concentrations of the retinoids lead to the production
of a thick layer of mucin, the inhibition of keratinization,
and the display of goblet cells.
In the absence of vitamin A, goblet mucous cells disappear
and are replaced by basal cells that have been stimulated to proliferate.
These undermine and replace the original epithelium with a stratified,
keratinizing epithelium. The suppression of normal secretions
leads to irritation and infection. Reversal of these changes is
achieved by the administration of retinol, retinoic acid, or other
retinoids. When this process happens in the cornea, severe hyperkeratinization
(xerophthalmia) may lead to permanent blindness.
Common causes of vitamin A deficiency include malnutrition and
bariatric surgery. Worldwide, xerophthalmia remains one of the most
common causes of blindness.
Mechanism of Action. In isolated fibroblasts or epithelial tissue,
retinoids enhance the synthesis of some proteins (e.g., fibronectin)
CHAPTER 64
OCULAR PHARMACOLOGY