section 38.1
Fat-Soluble Vitamins
pigment epithelial (RPE) cells. In the RPE cells involving
a series of reactions all
retinol is converted to
retinaldehyde which is transported to rod cells. In the rod
l-c/s retinaldehyde reassociates to form rhodopsin.
The importance of ABCR becomes evident in early onset
macular degeneration, due to mutations in the ABCR gene.
This disorder is known as
Stargardt’s disease,
an inherited
autosomal recessive disease, which affects one person in
10,000. Age-related macular degeneration in susceptible
individuals with risk factors (e.g., high lipid diet, smoking)
may also be due in part to defects in ABCR gene.
ABC transporters are involved in the transport of a wide
variety of molecules. For example, cystic fibrosis is caused
by a defective ABC transporter for chloride ion (cystic fi-
brosis transmembrane regulator, Chapter 12) and in
ier’s disease,
the abnormality of cholesterol efflux is due
to defects in an ABC protein (Chapter 20).
In the dark, the cation (Na+, Ca2+)-specific cGMP-
gated channels located in the rod outer segment (ROS) are
open, thus promoting the influx of Na+ and Ca2+. The
steady state of cations is maintained by outward pumping
ofCa2+ by theNa+/Ca2+ exchanger and Na+, K+-ATPase
pumps located in the inner segment. Exposure to light
blocks cGMP-gated cation channels, causing the inside of
the plasma membrane to become more negative and result-
ing in hyperpolarization. The signal of hyperpolarization
is transmitted to the synaptic body and eventually to the
brain. In the dark, because of the influx of Na+ and Ca2+,
the rod cells are depolarized and neurotransmitters (pos-
sibly aspartate or glutamate) are released from the presy-
naptic membrane of the rod cell at relatively high rates.
In the hyperpolarized state the neurotransmitter release is
inhibited. Thus, the postsynaptic bipolar cells are either
inhibited (hyperpolarized) or excited (depolarized).
Coupling of rhodopsin present in the disk membrane to
cation-specific cGMP-gated channels of the plasma mem-
brane involves signal amplification after photon absorp-
tion. The coupling mechanism (Figure 38-9) begins with
the absorption of light by
1 1
-cA-retinal-rhodopsin and
its conversion to all
retinal and the photoactivated
rhodopsin (R*). In the next step, activated rhodopsin ini-
tiates an amplification process that consists of activating
transducin, a signal-coupling G-protein. The active form
of transducin, Ta.GTP, activates cGMP-phosphodiesterase
(PDE). In the second amplification process, PDE hy-
drolyzes cGMP with the closure of cation channels. The
opening and closing of these cation channels that is me-
diated by cGMP is similar to Ca2+ ion channel gating by
cAMP in olfaction.
PDE belongs to a superfamily of enzymes that regu-
late cell function by maintaining cyclic nucleotide levels.
There are cAMP-specific PDEs (PDE4, PDE7, and PDE
L ig h t
R h odopsin-11 -cis retin a l (p re s e n t in th e d is c m e m b ra n e )
---------------------- *■ A ll-tra n s retin a l
P h o to a c tiv a te d R h o d o p s in (R *)
A m p lificatio n p ro c e s s
T ra n s d u c in (T)
' T gtp + T ;
P la s m a m e m b ra n e c a tio n c h a n n e ls clo su re;
D e c re a s e d C c f+ a n d N a * c o n c e n tra tio n ; h y p e rp o la riz a tio n
Mechanism for stimulus-response coupling of photon absorption to the
closure of plasma membrane cation channels. I, Inhibitory subunit of
cGMP-specific PDEs (PDE5, PDE
, and PDE9), and ones
specific for both cAMP and cGMP PDEs (PDE1, PDE2,
and PDE 10). Light induced-activated transducin activates
a cGMP-specific PDE, namely, PDE
. Another previously
discussed cGMP-specific PDE is PDE5, which is abundant
in vascular smooth muscle (Chapter 17). PDE5 is involved
in the nitric oxide and cGMP signaling pathway. A spe-
cific inhibitor of PDE5, sildenafil, causes increased blood
flow into the sinusoidal spaces of the corpus cavemosum
and corpus spongiosum, resulting in erection of the penis
(Chapter 17).
Photoactivation of rhodopsin produces a conforma-
tional change that allows it to interact with and activate
transducin, resulting in the replacement of GDP by GTP
at the
subunit. Metarhodopsin II (Figure 38-7) is the form
that interacts with transducin at the disk membrane sur-
face. Depending on the lifetime of the activated rhodopsin
molecule, each molecule can activate up to 500 transducin
molecules. The a-subunit GTP complex of transducin dis-
inhibits PDE by removing its inhibitor subunit (I), caus-
ing it to hydrolyze cGMP to 5'-GMP. The decrease in
cGMP concentration closes the plasma membrane cation
channels, decreasing Na+ and Ca2+ concentrations. Some
cases of
retinitis pigmentosa
are caused by mutations in
the transducin gene that prevent it from disinhibiting the
PDE, leading to an accumulation of cGMP that is toxic to
the retina. The transducin-GTP complex remains active as
long as the GTP bound to G„ is not hydrolyzed.
The recovery and adaptation of the rod and the cone
cells to the dark state begins shortly after illumination
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