328 Chapter 11
Phospholipase C–Ca^2 1
Second-Messenger System
The concentration of Ca^2 1 in the cytoplasm is kept very low by
the action of active transport carriers—calcium pumps—in the
plasma membrane. Through the action of these pumps, the con-
centration of Ca^2 1 in the cytoplasm is reduced to only about one
ten-thousandth of its concentration in the extra-cellular fluid. In
addition, the endoplasmic reticulum (chapter 3) of many cells
contains calcium pumps that actively transport Ca^2 1 from the
cytoplasm into the cisternae of the endoplasmic reticulum. The
steep concentration gradient for Ca^2 1 that results allows various
stimuli to evoke a rapid, though brief, diffusion of Ca^2 1 into
the cytoplasm, which can serve as a signal in different control
systems.
At the terminal boutons of axons, for example, the entry
of Ca^2 1 through voltage-regulated Ca^2 1 channels in the plasma
membrane serves as a signal for the release of neurotransmitters
(chapter 7; see fig. 7.23). Similarly, when muscles are stimulated
to contract, Ca^2 1 couples electrical excitation of the muscle cell to
the mechanical processes of contraction (chapter 12, section 12.2).
Additionally, it is now known that Ca^2 1 serves as a part of a
second-messenger system in the action of a number of hormones.
When epinephrine stimulates its target organs, it must first
bind to adrenergic receptor proteins in the plasma membrane of
its target cells. As discussed in chapter 9, there are two types of
adrenergic receptors—alpha and beta (see fig. 9.10). Stimulation
of the beta-adrenergic receptors by epinephrine results in activa-
tion of adenylate cyclase and the production of cAMP. Stimula-
tion of alpha 1 -adrenergic receptors by epinephrine, in contrast,
activates the target cell via the Ca^2 1 second-messenger system
(see fig. 11.10 ).
The binding of epinephrine to its alpha-adrenergic recep-
tor activates, via G-proteins, an enzyme in the plasma mem-
brane known as phospholipase C ( fig. 11.9 ). The substrate of
this enzyme, a particular membrane phospholipid, is split by
the active enzyme into inositol triphosphate (IP 3 ) and another
derivative, diacylglycerol (DAG). Both derivatives serve as
second messengers with a great diversity of functions, but it is
IP 3 that acts to increase cytoplasmic Ca^2 1 in response to hor-
mone stimulation and will be discussed here.
The IP 3 leaves the plasma membrane and diffuses through the
cytoplasm to the endoplasmic reticulum. The membrane of the
endoplasmic reticulum contains receptor proteins for IP 3 ; the IP 3
is a second messenger in its own right, carrying the hormone’s
message from the plasma membrane to the endoplasmic reticu-
lum. Binding of IP 3 to its receptors causes specific Ca^2 1 channels
to open, so that Ca^2 1 diffuses out of the endoplasmic reticulum
and into the cytoplasm ( fig. 11.9 ).
As a result of these events, there is a rapid and transient
rise in the cytoplasmic Ca^2 1 concentration. This signal is aug-
mented, through mechanisms that are incompletely understood,
by the opening of Ca^2 1 channels in the plasma membrane.
This may be due to the action of yet a different (and currently
unknown) messenger sent from the endoplasmic reticulum
to the plasma membrane. The Ca^2 1 that enters the cytoplasmby phosphodiesterase, an enzyme within the target cells that
hydrolyzes cAMP into an inactive form. Through the action
of phosphodiesterase, the stimulatory effect of a hormone that
uses cAMP as a second messenger depends upon the continu-
ous generation of new cAMP molecules, and thus depends on
the level of secretion of the hormone.
In addition to cyclic AMP, cyclic guanosine monophosphate
(cGMP) functions as a second messenger in certain cases. For exam-
ple, the regulatory molecule nitric oxide (discussed in chapter 7
and in section 11.7 of this chapter) exerts its effects on smooth
muscle by stimulating the production of cGMP in its target cells.
One example of this is the vascular smooth muscle relaxation that
produces erection of the penis (see chapter 20, fig. 20.21). Indeed,
as illustrated in this figure, the drug Viagra helps treat erectile dys-
function by inhibiting the phosphodiesterase enzyme that breaks
down cGMP.
CLINICAL APPLICATION
Methyxanthines are a chemical class that includes both
theophylline —found naturally in cocoa beans and tea—and
caffeine. These compounds block adenosine receptors (not
discussed here) and inhibit phosphodiesterase. Theophyl-
line is sometimes used medically as a supplementary treat-
ment for asthma, if the person is already taking an inhaled
b 2 -agonist drug (promoting bronchodilation; see chapter 9)
and a corticosteroid to reduce inflammation. Theophylline
inhibition of phosphodiesterase raises the cAMP levels in
the cell, enhancing the stimulation of cAMP production by
epinephrine’s activation of the b 2 -adrenergic receptors in
the bronchioles and promoting bronchodilation. However,
raising cAMP levels in myocardial cells duplicates epineph-
rine action in the heart, causing increased cardiac rate
and strength of contraction. Theophylline also has anti-
inflammatory effects that can be beneficial in the treatment
of asthma.- The hormone binds to its receptor on the outer surface of the
target cell’s plasma membrane. - Hormone-receptor interaction acts by means of G-proteins to
stimulate the activity of adenylate cyclase on the cytoplasmic
side of the membrane. - Activated adenylate cyclase catalyzes the conversion of ATP to
cyclic AMP (cAMP) within the cytoplasm. - Cyclic AMP activates protein kinase enzymes that were already
present in the cytoplasm in an inactive state. - Activated cAMP-dependent protein kinase transfers phosphate
groups to (phosphorylates) other enzymes in the cytoplasm. - The activity of specific enzymes is either increased or inhibited
by phosphorylation. - Altered enzyme activity mediates the target cell’s response to
the hormone.
Table 11.4 | Sequence of Events Involving
Cyclic AMP as a Second Messenger