CHAPTER 2Overview of Cellular Physiology in Medical Physiology 43until activated by the cellular machinery. The net result is
DNA fragmentation, cytoplasmic and chromatin condensa-
tion, and eventually membrane bleb formation, with cell
breakup and removal of the debris by phagocytes (see Clinical
Box 2–2).
TRANSPORT ACROSS
CELL MEMBRANES
There are several mechanisms of transport across cellular
membranes. Primary pathways include exocytosis, endocyto-
sis, movement through ion channels, and primary and secon-
dary active transport. Each of these are discussed below.
EXOCYTOSIS
Vesicles containing material for export are targeted to the cell
membrane (Figure 2–11), where they bond in a similar man-
ner to that discussed in vesicular traffic between Golgi stacks,
via the v-SNARE/t-SNARE arrangement. The area of fusion
then breaks down, leaving the contents of the vesicle outside
and the cell membrane intact. This is the Ca2+-dependent pro-
cess of exocytosis (Figure 2–12).
Note that secretion from the cell occurs via two pathways
(Figure 2–11). In the nonconstitutive pathway, proteins from
the Golgi apparatus initially enter secretory granules, where
processing of prohormones to the mature hormones occurs
before exocytosis. The other pathway, the constitutive path-
way, involves the prompt transport of proteins to the cell
membrane in vesicles, with little or no processing or storage.
The nonconstitutive pathway is sometimes called the regu-
lated pathway, but this term is misleading because the output
of proteins by the constitutive pathway is also regulated.
ENDOCYTOSIS
Endocytosis is the reverse of exocytosis. There are various
types of endocytosis named for the size of particles being in-
gested as well as the regulatory requirements for the particular
process. These include phagocytosis, pinocytosis, clathrin-
mediated endocytosis, caveolae-dependent uptake, and
nonclathrin/noncaveolae endocytosis.
Phagocytosis (“cell eating”) is the process by which bacteria,
dead tissue, or other bits of microscopic material are engulfed
by cells such as the polymorphonuclear leukocytes of the blood.
The material makes contact with the cell membrane, which
then invaginates. The invagination is pinched off, leaving the
engulfed material in the membrane-enclosed vacuole and the
cell membrane intact. Pinocytosis (“cell drinking”) is a similar
process with the vesicles much smaller in size and the sub-
stances ingested are in solution. The small size membrane that
is ingested should not be misconstrued; cells undergoing active
pinocytosis (eg, macrophages) can ingest the equivalent of their
entire cell membrane in just 1 hour.
Clathrin-mediated endocytosis occurs at membrane inden-
tations where the protein clathrin accumulates. Clathrin mole-
cules have the shape of triskelions, with three “legs” radiating
from a central hub (Figure 2–13). As endocytosis progresses,CLINICAL BOX 2–2
Molecular Medicine
Fundamental research on molecular aspects of genetics,
regulation of gene expression, and protein synthesis has
been paying off in clinical medicine at a rapidly accelerat-
ing rate.
One early dividend was an understanding of the mecha-
nisms by which antibiotics exert their effects. Almost all act
by inhibiting protein synthesis at one or another of the
steps described previously. Antiviral drugs act in a similar
way; for example, acyclovir and ganciclovir act by inhibiting
DNA polymerase. Some of these drugs have this effect pri-
marily in bacteria, but others inhibit protein synthesis in the
cells of other animals, including mammals. This fact makes
antibiotics of great value for research as well as for treat-
ment of infections.
Single genetic abnormalities that cause over 600 human
diseases have now been identified. Many of the diseases
are rare, but others are more common and some cause
conditions that are severe and eventually fatal. Examples
include the defectively regulated Cl– channel in cystic fibro-
sis and the unstable trinucleotide repeats in various parts
of the genome that cause Huntington’s disease, the fragile
X syndrome, and several other neurologic diseases. Abnor-
malities in mitochondrial DNA can also cause human dis-
eases such as Leber’s hereditary optic neuropathy and
some forms of cardiomyopathy. Not surprisingly, genetic
aspects of cancer are probably receiving the greatest cur-
rent attention. Some cancers are caused by oncogenes,
genes that are carried in the genomes of cancer cells and
are responsible for producing their malignant properties.
These genes are derived by somatic mutation from closely
related proto-oncogenes, which are normal genes that
control growth. Over 100 oncogenes have been described.
Another group of genes produce proteins that suppress tu-
mors, and more than 10 of these tumor suppressor genes
have been described. The most studied of these is the p53
gene on human chromosome 17. The p53 protein pro-
duced by this gene triggers apoptosis. It is also a nuclear
transcription factor that appears to increase production of
a 21-kDa protein that blocks two cell cycle enzymes, slow-
ing the cycle and permitting repair of mutations and other
defects in DNA. The p53 gene is mutated in up to 50% of
human cancers, with the production of p53 proteins that
fail to slow the cell cycle and permit other mutations in
DNA to persist. The accumulated mutations eventually
cause cancer.