Ganong's Review of Medical Physiology, 23rd Edition

38
SECTION I
Cellular & Molecular Basis of Medical Physiology

CELL ADHESION MOLECULES

Cells are attached to the basal lamina and to each other by
cell
adhesion molecules (CAMs)
that are prominent parts of the
intercellular connections described below. These adhesion
proteins have attracted great attention in recent years because
of their unique structural and signaling functions found to be
important in embryonic development and formation of the
nervous system and other tissues, in holding tissues together
in adults, in inflammation and wound healing, and in the me-
tastasis of tumors. Many CAMs pass through the cell mem-
brane and are anchored to the cytoskeleton inside the cell.
Some bind to like molecules on other cells (homophilic bind-
ing), whereas others bind to nonself molecules (heterophilic
binding). Many bind to
laminins,
a family of large cross-
shaped molecules with multiple receptor domains in the ex-
tracellular matrix.
Nomenclature in the CAM field is somewhat chaotic, partly
because the field is growing so rapidly and partly because of
the extensive use of acronyms, as in other areas of modern
biology. However, the CAMs can be divided into four broad
families: (1)
integrins,
heterodimers that bind to various
receptors; (2) adhesion molecules of the
IgG superfamily
of
immunoglobulins; (3)
cadherins,
Ca
2+
-dependent molecules
that mediate cell-to-cell adhesion by homophilic reactions;
and (4)
selectins,
which have lectin-like domains that bind
carbohydrates. Specific functions of some of these molecules
are addressed in later chapters.
The CAMs not only fasten cells to their neighbors, but they
also transmit signals into and out of the cell. For example,
cells that lose their contact with the extracellular matrix via
integrins have a higher rate of apoptosis than anchored cells,
and interactions between integrins and the cytoskeleton are
involved in cell movement.

INTERCELLULAR CONNECTIONS

Intercellular junctions that form between the cells in tissues
can be broadly split into two groups: junctions that fasten the
cells to one another and to surrounding tissues, and junctions
that permit transfer of ions and other molecules from one cell
to another. The types of junctions that tie cells together and
endow tissues with strength and stability include
tight junc-
tions,
which are also known as the
zonula occludens
(Figure
2–8). The
desmosome
and
zonula adherens
also help to hold
cells together, and the
hemidesmosome
and
focal adhesions
attach cells to their basal laminas. The
gap junction
forms a
cytoplasmic “tunnel” for diffusion of small molecules (< 1000
Da) between two neighboring cells.
Tight junctions characteristically surround the apical mar-
gins of the cells in epithelia such as the intestinal mucosa, the
walls of the renal tubules, and the choroid plexus. They are
also important to endothelial barrier function. They are
made up of ridges—half from one cell and half from the
other—which adhere so strongly at cell junctions that they

almost obliterate the space between the cells. There are three

main families of transmembrane proteins that contribute to

tight junctions:

occludin, junctional adhesion molecules

(JAMs),

and

claudins;

and several more proteins that inter-

act from the cytosolic side. Tight junctions permit the pas-

sage of some ions and solute in between adjacent cells

(paracellular pathway)

and the degree of this “leakiness”

varies, depending in part on the protein makeup of the tight

junction. Extracellular fluxes of ions and solute across epithe-

lia at these junctions are a significant part of overall ion and

solute flux. In addition, tight junctions prevent the move-

ment of proteins in the plane of the membrane, helping to

maintain the different distribution of transporters and chan-

nels in the apical and basolateral cell membranes that make

transport across epithelia possible.

In epithelial cells, each zonula adherens is usually a contin-

uous structure on the basal side of the zonula occludens, and

it is a major site of attachment for intracellular microfila-

ments. It contains cadherins.

Desmosomes are patches characterized by apposed thicken-

ings of the membranes of two adjacent cells. Attached to the

thickened area in each cell are intermediate filaments, some

running parallel to the membrane and others radiating away

from it. Between the two membrane thickenings the intercellu-

lar space contains filamentous material that includes cadherins

and the extracellular portions of several other transmembrane

proteins.

Hemidesmosomes look like half-desmosomes that attach

cells to the underlying basal lamina and are connected

FIGURE 2–8 Intercellular junctions in the mucosa of the small

intestine. Tight junctions (zonula occludens), adherens junctions

(zonula adherens), desmosomes, gap junctions, and hemidesmosomes

are all shown in relative positions in a polarized epithelial cell.

Tight

junction

(zonula

occludens)

Zonula

adherens

Desmosomes

Gap

junctions

Hemidesmosome