The Endocrine System
can catalyze hundreds of reactions. As the reaction cascades
through one enzyme intermediate aFer another, the number of
product molecules increases dramatically at each step. A single
hormone molecule binding to a receptor can generate millions
of ﬁnal product molecules!
Te sequence of reactions set into motion by cAMP depends
on the type of target cell, the speciﬁc protein kinases it contains,
and the substrates within that cell available for phosphorylation
by the protein kinase. ±or example, in thyroid cells, binding of
thyroid-stimulating hormone promotes synthesis of the thyroid
hormone thyroxine; in liver cells, binding of glucagon activates
enzymes that break down glycogen, releasing glucose to the
blood. Since some G proteins inhibit rather than activate ade-
nylate cyclase, thereby reducing the cytoplasmic concentration
of cAMP, even slight changes in levels of antagonistic hormones
can inﬂuence a target cell’s activity.
Te action of cAMP persists only brieﬂy because the mol-
ecule is rapidly degraded by the intracellular enzyme
. While at ﬁrst glance this may appear to be a
problem, it is quite the opposite. Because of the ampliﬁcation
eﬀect, most hormones need to be present only brieﬂy to cause
results, and the quick work of phosphodiesterase means that no
extracellular controls are necessary to stop the activity. It’s the
continued presence of hormones that maintains their continued
action, if that is needed.
-Calcium Signaling Mechanism
While cyclic AMP
is the activating second messenger for many hormones, other
hormones use diﬀerent second messengers. ±or example, in the
-calcium signaling mechanism, intracellular calcium ions
act as a second messenger.
Like the cAMP signaling mechanism, the PIP
naling mechanism involves a G protein (G
) and a membrane-
bound eﬀector, in this case an enzyme called
Phospholipase C splits a plasma membrane phospholipid called
hosphate) into two second
. DAG, like cAMP, activates a protein kinase enzyme,
which triggers responses within the target cell. In addition, IP
from intracellular storage sites.
Te liberated Ca
also takes on a second-messenger role,
either by directly altering the activity of speciﬁc enzymes and
channels or by binding to the intracellular regulatory protein
. Once Ca
binds to calmodulin, it activates en-
zymes that amplify the cellular response.
Other Signaling Mechanisms
Other hormones that bind plasma
membrane receptors act on their target cells through diﬀerent
signaling mechanisms. ±or example, cyclic guanosine monophos-
phate (cGMP) is a second messenger for selected hormones.
Still other hormones, such as insulin and certain growth fac-
tors, work without second messengers. Te insulin receptor is a
enzyme that is activated by autophosphorylation
(addition of phosphate to several of its own tyrosines) when
insulin binds. Te activated insulin receptor provides docking
sites for intracellular
that, in turn, initiate a series
of protein phosphorylations that trigger speciﬁc cell responses.
Intracellular Receptors and Direct Gene Activation
Being lipid soluble, steroid hormones (and, strangely, thyroid
hormone, a small iodinated amine) diﬀuse into their target
cells where they bind to and activate an intracellular receptor
. Te activated receptor-hormone complex then
makes its way to the nuclear chromatin and binds to a speciﬁc
region of DNA. (Tere are exceptions to these generalizations.
±or example, thyroid hormone receptors are always bound to
DNA even in the absence of thyroid hormone.)
When the receptor-hormone complex binds to DNA, it
“turns on” a gene; that is, it prompts transcription of DNA to
produce a messenger RNA (mRNA). Te mRNA is then trans-
lated on the cytoplasmic ribosomes, producing speciﬁc proteins.
Tese proteins include enzymes that promote the metabolic ac-
tivities induced by that particular hormone and, in some cases,
promote synthesis of either structural proteins or proteins to be
exported from the target cell.
Target Cell Speciﬁcity
In order for a target cell to respond to a hormone, the cell must
receptor proteins on its plasma membrane or in
its interior to which that hormone can bind. ±or example, re-
ceptors for adrenocorticotropic hormone (AC²H) are normally
found only on certain cells of the adrenal cortex. By contrast,
thyroxine is the principal hormone stimulating cellular metabo-
lism, and nearly all body cells have thyroxine receptors.
A hormone receptor responds to hormone binding by
prompting the cell to perform, or turn on, some gene-determined
“preprogrammed” function. As such, hormones are molecular
triggers rather than informational molecules. Although binding
of a hormone to a receptor is the crucial ﬁrst step, target cell acti-
vation depends equally on three other factors: (1) blood levels of
the hormone, (2) relative numbers of receptors for that hormone
on or in the target cells, and (3)
(strength) of the binding
between the hormone and the receptor.
Te ﬁrst two factors change rapidly in response to various
stimuli and changes within the body. As a rule, for a given level
of hormone in the blood, a large number of high-aﬃnity re-
ceptors produces a pronounced hormonal eﬀect, and a smaller
number of low-aﬃnity receptors reduces the target cell response
or causes outright endocrine dysfunction.
Receptors are dynamic structures. ±or example, persistently
low levels of a hormone can cause its target cells to form addi-
tional receptors for that hormone. Tis is called
Likewise, prolonged exposure to high hormone concentrations
can decrease the number of receptors for that hormone. Tis
desensitizes the target cells, so they respond
less vigorously to hormonal stimulation, preventing them from
overreacting to persistently high hormone levels. Additionally,
receptors can be uncoupled from their signaling mechanism,
altering the sensitivity of the response.
Hormones inﬂuence not only the number of their own receptors
but also the number of receptors that respond to other hormones.
±or example, progesterone down-regulates estrogen receptors in
the uterus, thus antagonizing estrogen’s actions. On the other hand,