718
chapter 30
Endocrine Metabolism I: Introduction
is caused by hyperfunctioning of MSH receptors coupled
to
Gsa
in the melanocytes.
An example of decreased function due to impaired ac-
tivation or loss of Gsa and resistance to hormone action
is pseudohypoparathyroidism
{Albright’s hereditary os-
teodystrophy).
Patients with this syndrome exhibit gen-
eralized resistance to the action of those hormones de-
pendent on GSa for their function despite elevated serum
hormone levels. Several dysmorphic features are also char-
acteristic of these patients.
A well-understood disorder of hypofunctioning Gsa
is
pseudohypoparathyroidism type la.
This disorder ex-
hibits a dominant inheritance pattern with one normal and
one abnormal Gs„ allele. In different families affected
by pseudohypoparathyroidism la, two missense muta-
tions have been identified in Gsa: Arg
3 8 5
—>■
His and
Arg
2 3 1
—»■
His. The former mutation prevents receptor-
mediated Gs stimulation and the latter mutation prevents
receptor-mediated binding of GTP to Gs. A paradoxical
finding consisting of both gain and loss of function due to
identical mutations in Gs„ (Ala
3 6 6
-> Ser), in two unrelated
boys with pseudohypoparathyroidism la. Both of these
patients, while exhibiting hormone resistance in some tis-
sues, showed autonomous production of testosterone by
testicular Leydig cells due to gain of function in the re-
ceptors of luteinizing hormone. This results in preco-
cious puberty
{testotoxicosis).
This particular mutation
in the Gs„ gene involves a gain in function property in
Gsa enhancing the rate of release of GDP. However, the
paradoxical effect is due to temperature stability. The mu-
tant protein is unstable at 37°C, which causes pseudo-
hypoparathyroidism; however, the mutant protein is sta-
ble at lower temperature and thus is active in testes,
which are about 3°C-5°C cooler than the rest of the
body.
G-protein abnormalities also may arise from mutations
in genes encoding proteins that regulate G-protein sig-
naling. Several RGSs have been identified. RGS proteins
bind to G„ and accelerate the hydrolysis of GTP. The phys-
iological responses of G-proteins regulated by RGSs are
fast and include vagal slowing of the heart rate
( G j) ,
reti-
nal detection of photones (Gt), and contraction of vascular
smooth muscle
( G q ).
G-Protein-Coupled Phosphatidylinositol-
Ca2+ Pathway
The calcium system is more complex than the cAMP sys-
tem and contains a variety of mechanisms for transduc-
ing the Ca2+ signal into changes in cellular function. It
is also sensitive and responds to relatively small, tran-
sient changes in free Ca2+ concentration. This sensitivity
is desirable from a regulatory point of view, but it also
reflects the toxicity of even low concentrations of free
Ca2+ (Chapter 37).
In a resting cell, the pool of cytosolic calcium is very
small, and most of the intracellular Ca2+ is bound in mito-
chondria or the endoplasmic reticulum or is bound to the
plasma membrane. The cytosolic calcium ion concentra-
tion is ~ 0.1 /zmol/L, in contrast to the high concentra-
tion (~ 1000 /zmol/L) outside cells. This 10,000-fold gra-
dient is maintained by the plasma membrane, which is
relatively impermeable to calcium; by an ATP-dependent
Ca2+ pump (which extrudes Ca2+ in exchange for H+)
in the plasma membrane; and by “pump-leak” systems in
the endoplasmic reticulum and inner mitochondrial mem-
branes. A change in the permeability of any of these mem-
branes alters the calcium flux across the membrane and
causes a change in cytosolic calcium concentration. This
change is thought to act as the messenger in the calcium
system. Plasma membranes regulate cytosolic calcium
concentration by their role as a diffusion barrier and by
containing the ATP-dependent Ca2+ pump and receptors
for extracellular messengers. Activation of some of these
receptors increases the Ca2+ permeability of the plasma
membrane and thus the level of cytosolic calcium. In other
cases, the activated receptor produces one or more sec-
ond messengers that increase cytosolic Ca2+ concentra-
tion from the calcium pool in the endoplasmic reticulum.
Calcium then becomes a “third messenger.” The endoplas-
mic reticulum is the source of Ca2+ in the initial phase of
cell activation by some hormones in many systems. Since
the plasma membrane can bind Ca2+, the rise in cytosolic
calcium following binding of some extracellular messen-
gers may be due to release from this intracellular calcium
pool.
The inner mitochondrial membrane may function pri-
marily as a calcium sink, taking up excess calcium in the
cytosol that results from hormonal activation of the cell.
At cytosolic Ca2+ concentrations greater than 0.6 /zmol/L,
the mitochondrial calcium pump is activated and stores
calcium in the mitochondrial matrix as a nonionic, rapidly
exchangeable, phosphate salt. At low cytosolic calcium
concentrations, the inner mitochondrial membrane allows
Ca2+ to “leak” into the cytosol. The capacity of the active
influx pathway (the pump) is much greater than that of the
passive efflux route (the leak). The mitochondrial pump-
leak system may serve to fine-tune the cytosolic calcium
concentration while the plasma membrane is the principal
safeguard against entry of toxic amounts of calcium into
the cell.
Mechanism of the Calcium Messenger System
Most extracellular messengers that cause a rise in cy-
tosolic Ca2+ concentration also increase the turnover
