Cell Receptors
Signaling systems consist of
receptors that reside either in the cell membrane (surface receptors) or within
the cells (intracellular receptors). Receptors are activated by a variety of
extracellular signals or first messengers, including neurotransmitters,
protein hormones and growth factors, steroids, and other chemical messengers.
Some lipid-soluble chemical messengers move through the membrane and bind to
cytoplasmic or nuclear receptors to exert their physiologic effects. Signaling
systems also include transducers and effectors that are involved in conversion
of the signal into a physiologic response. The pathway may include additional
intracellular mechanisms, called second messengers. Many molecules
involved in signal transduction are proteins. A unique property of proteins
that allows them to function in this way is their ability to change their shape
or conformation, thereby changing their function and consequently the functions
of the cell. Proteins often accomplish these conformational changes through
enzymes called protein kinases that catalyze the phosphorylation of
amino acids in the protein structure.
Cell Surface Receptors
Each cell type in the body contains
a distinctive set of surface receptors that enable it to respond to a
complementary set of signaling molecules in a specific, preprogrammed way.
These proteins are not static components of the cell membrane; they increase or
decrease in number according to the needs of the cell. When excess chemical
messengers are present, the number of active receptors decreases in a process
called down-regulation; when there is a deficiency of the messenger, the
number of active receptors increases through up-regulation. Three known
classes of cell surface receptor proteins exist: G-protein–linked,
ion-channel–linked, and enzyme-linked.
G-Protein–Linked Receptors. With more than a 1000 members, G-protein–linked
receptors are the largest
family of cell surface receptors. Although many intercellular messengers
exist, they rely on the intermediary activity of a separate class of
membrane-bound regulatory proteins to convert external signals (first
messengers) into internal signals (second messengers). Because these regulatory
proteins bind to guanine nucleotides such as guanine diphosphate (GDP) and
guanine triphosphate (GTP), they are called G proteins. G-protein–linked
receptors mediate cellular responses for numerous types of first messengers,
including proteins, small peptides, amino acids, and fatty acid derivatives
such as the prostaglandins.
Although there are differences
among the G-protein–linked receptors, all share a number of features. They all
have a ligand-binding extracellular receptor component, which functions as a
signal discriminator by recognizing a specific first messenger, and they all
undergo conformational changes with receptor binding that activates the G
protein (Fig. 4.10). All G
proteins are found on the cytoplasmic side of the cell membrane, and all incorporate the GTPase cycle, which
functions as a molecular switch that exists in two states. In its activated
(on) state, the G protein has a high affinity for GTP, and in its inactivated
(off) state, it binds GDP.
At the molecular level, G proteins
are heterotrimeric (i.e., they have three subunits) proteins (see Fig.
4.10). The three subunits are designated alpha (α), beta (β), and gamma (γ).
The α subunit can bind either GDP or GTP and contains the GTPase activity.
GTPase is an enzyme that converts GTP with its three phosphate groups to GDP
with its two phosphate groups.
When GDP is bound to the α subunit,
the G protein is inactive; when GTP is bound, it is active. The activated G
protein has GTPase activity, so eventually the bound GTP is hydrolyzed to GDP,
and the G protein reverts to its inactive state. Receptor activation causes the
α subunit to dissociate from the receptor and the β and γ subunits and transmit
the signal from the first messenger to its effector protein. Often, the
effector is an enzyme that converts an inactive precursor molecule into a
second messenger, which diffuses into the cytoplasm and carries the signal
beyond the cell membrane. A common second messenger is cyclic adenosine monophosphate
(cAMP). It is
activated by the
enzyme adenylyl cyclase,
which generates cAMP by
transferring phosphate groups from ATP to other proteins. This transfer changes
the conformation and function of these proteins. Such changes eventually
produce the cell response to the first messenger, whether it is a secretion,
muscle contraction or relaxation, or a change in metabolism. Sometimes, it is
the opening of membrane channels involved in calcium or potassium influx.
Enzyme-Linked Receptors. Like G-protein–linked receptors, enzyme-linked
receptors are transmembrane proteins with their ligand-binding site on the
outer surface of the cell membrane. Instead of having a cytosolic domain that
associates with a G protein, their cytosolic domain either has intrinsic enzyme
activity or associates directly with an enzyme. There are several classes of
enzyme-linked receptors, including those that activate or have tyrosine kinase
activity. Enzyme-linked receptors mediate cellular responses such as calcium
influx, increased sodium–potassium exchange, and stimulation of glucose and
amino acid uptake. Insulin, for example, acts by binding to a surface receptor
with tyrosine kinase activity.
The signaling cascades generated by
the activation of tyrosine kinase
receptors are also involved in the function of growth factors. As their name
implies, many growth factors are important messengers in signaling cell
replacement and cell growth. Most of the growth factors belong to one of three
groups: factors that foster the multiplication and development of various cell
types (e.g., epidermal growth factor and vascular endothelial growth
factor); cytokines, which are important in the regulation of the immune system;
and colony-stimulating factors, which regulate the proliferation and maturation
of white and red blood cells. All growth factors function by binding to
specific receptors that deliver signals to target cells. These signals have two
general effects: they stimulate the transcription of many genes that were
silent in resting cells, and they regulate the entry of cells into the cell
cycle and their passage through the cell cycle.
Ion-Channel–Linked Receptors. Ion-channel–linked receptors are involved in
the rapid synaptic signaling between electrically excitable cells. Many
neurotransmitters mediate this type of signaling by transiently opening or
closing ion channels formed by integral proteins in the cell membrane. This
type of signaling is involved in the transmission of impulses in nerve and
muscle cells.
Intracellular Receptors
Some messengers, such as thyroid
hormone and steroid hormones, do not bind to membrane receptors but move
directly across the lipid layer of the cell membrane and are
carried to the cell nucleus, where they influence DNA activity. Many of
these hormones bind to a cytoplasmic receptor, and the receptor–hormone complex is carried to the
nucleus. In the nucleus, the receptor–hormone complex binds
to DNA, thereby increasing
transcription of mRNA. The mRNAs are translated in the ribosomes, with the
production of increased amounts of
proteins that alter cell function.
