Download General Principles

CELL SIGNALING
Gap Junctions Allow Signaling Information to
Be Shared by Neighboring Cells
• These are specialized cell-cell junctions that can
form between closely apposed plasma
membranes, directly connecting the cytoplasms of
the joined cells via narrow water-filled channels
• The channels allow the exchange of small
intracellular signaling molecules ( intracellular
mediators), such as Ca2+ and cyclic AMP, but not
of macromolecules, such as proteins or nucleic
acids
• Thus cells connected by gap junctions can
communicate with each other directly without
having to deal with the barrier presented by the
plasma membranes
Each Cell Is Programmed to Respond to Specific
Combinations of Signaling Molecules
• Any given cell in a multicellular organism is exposed to many perhaps hundreds - of different signals from its environment
• Thus a cell may be programmed to respond to one set of
signals by differentiating, to another set by proliferating, and
to yet another by carrying out some specialized function
• Most cells in higher animals, moreover, are programmed to
depend on a specific set of signals simply for survival: when
deprived of the appropriate signals a cell will activate a
suicide program and kill itself - a process called programmed
cell death
• Different types of cells require different sets of survival signals
and so are restricted to different environments in the body
• Because signaling molecules generally act in combinations, an
animal can control the behavior of its cells in highly specific
ways using a limited diversity of such molecules: hundreds of
such signals can be used in millions of combinations
(Combinational Signaling)
Different Cells Can Respond Differently to the
Same Chemical Signal
• TWO specific ways, a cell reacts to its environment
1. According to the set of receptor proteins that the cell
possesses through which it is tuned to detect a particular
subset of the available signals and,
2. According to the intracellular machinery by which the cell
integrates and interprets the information that it receives
• The neurotransmitter acetylcholine, for example, stimulates
the contraction of skeletal muscle cells but decreases the rate
and force of contraction in heart muscle cells
• Difference may lie in different types of receptors and also
different internal machinery (in case of identical receptors
being used)
The Concentration of a Molecule Can Be
Adjusted Quickly Only If the Lifetime of the
Molecule Is Short
• It is important to consider what happens when a signal
is withdrawn
• Many intracellular proteins that are rapidly degraded
have short half-lives, some surviving less than 10
minutes; in most cases these are proteins with key
regulatory roles, whose concentrations are rapidly
regulated in the cell by changes in their rates of
synthesis
• Likewise, any covalent modifications of proteins that
occur as part of a rapid signaling process - most
commonly the addition of a phosphate group to an
amino acid side chain - must be continuously removed
at a rapid rate to make such signaling possible
Nitric Oxide Gas Signals by Binding Directly to
an Enzyme Inside the Target Cell
• Nitric oxide (NO), has recently been recognized to
act as a signaling molecule in vertebrates
• Acetylcholine acts indirectly by inducing the
endothelial cells to make and release NO, which
then signals the smooth muscle cells to relax (
nitroglycerine – treatment of angina)
• NO is also produced as a local mediator by
activated macrophages and neutrophils to help
them kill invading microorganisms.
• In addition, it is used by many types of nerve cells
to signal neighboring cells
• NO is made by the enzyme NO synthase by the
deamination of the amino acid arginine.
• Because it diffuses readily across membranes,
the NO diffuses out of the cell where it is
produced and passes directly into neighboring
cells
• It acts only locally because it has a short half-life about 5- 10 seconds
• The effects of NO can be rapid, occurring within
seconds
• In many target cells, such as endothelial cells, NO
reacts with iron in the active site of the enzyme
guanylyl cyclase, stimulating it to produce the
intracellular mediator cyclic GMP
Steroid Hormones, Thyroid Hormones, Retinoids, and
Vitamin D Bind to Intracellular Receptors That Are
Ligand activated Gene Regulatory Proteins
• Steroid hormones, thyroid hormones, retinoids, and vitamin D
are small hydrophobic molecules that differ greatly from one
another in both chemical structure and function
• They diffuse directly across the plasma
membrane of target cells and bind to
intracellular receptor proteins.
• Ligand binding activates the receptors, which
then directly regulate the transcription of
specific genes.
• These receptors are structurally related and
constitute the intracellular receptor
superfamily (or steroid-hormone receptor
superfamily)
• Steroid hormones, including cortisol, the steroid sex
hormones, vitamin D (in vertebrates), and the moulting
hormone ecdysone (in insects), are all made from
cholesterol
• Besides the fundamental difference in the way they signal
their target cells, most water-insoluble signaling molecules
differ from water-soluble ones in the length of time that
they persist in the bloodstream or tissue fluids.
• Most water-soluble hormones are removed and/or broken
down within minutes of entering the blood, and local
mediators and neurotransmitters are removed from the
extracellular space even faster - within seconds or
milliseconds.
• Steroid hormones, by contrast, persist in the blood for
hours and thyroid hormones for days.
• Consequently, water soluble signaling molecules usually
mediate responses of short duration, whereas the water
insoluble ones tend to mediate longer-lasting responses.
• The intracellular receptors for the steroid and
thyroid hormones, retinoids, and vitamin D all
bind to specific DNA sequences adjacent to the
genes that the ligand regulates
• Ligand binding alters the conformation of the
receptor protein, which then activates (or
occasionally suppresses) gene transcription.
• In many cases the response takes place in two
steps:
1. The direct induction of the transcription of a
small number of specific genes within about 30
minutes is known as the primary response;
2. The products of these genes in turn activate
other genes and produce a delayed, secondary
response.
There Are Three Known Classes of Cell-Surface
Receptor Proteins
• Ion-channel-linked receptors, also known as
transmitter-gated ion channels, are involved in rapid
synaptic signaling between electrically excitable cells.
• This type of signaling is mediated by a small number of
neurotransmitters that transiently open or close the
ion channel formed by the protein to which they bind,
briefly changing the ion permeability of the plasma
membrane and thereby the excitability of the
postsynaptic cell.
• The ion-channel linked receptors belong to a family of
homologous, multipass transmembrane proteins
• G-protein-linked receptors act indirectly to regulate the
activity of a separate plasma-membrane bound target
protein, which can be an enzyme or an ion channel.
• The interaction between the receptor and the target
protein is mediated by a third protein, called a trimeric
GTP-binding regulatory protein (G protein)
• The activation of the target protein either alters the
concentration of one or more intracellular mediators (if the
target protein is an enzyme) or alters the ion permeability
of the plasma membrane (if the target protein is an ion
channel).
• The intracellular mediators act in turn to alter the behavior
of yet other proteins in the cell.
• All of the G protein- linked receptors belong to a large
superfamily of homologous, seven-pass transmembrane
proteins
• Enzyme-linked receptors, when activated,
either function directly as enzymes or are
associated with enzymes
• Most are single-pass transmembrane proteins,
with their ligand binding site outside the cell
and their catalytic site inside.
• Compared with the other two classes,
enzyme-linked receptors are heterogeneous,
although the great majority are protein
kinases, or are associated with protein
kinases, that phosphorylate specific sets of
proteins in the target cell
Activated Cell-Surface Receptors Trigger PhosphateGroup Additions to a Network of Intracellular
Proteins
• Signals received at the surface of a cell by GPL and EL classes of
receptors are often relayed to the nucleus, where they alter the
expression of specific genes and thereby alter the behavior of
the cell.
• Elaborate sets of intracellular signaling proteins form the relay
systems. The majority of these proteins are of one of two kinds:
• Proteins that become phosphorylated by protein kinases, and
• Proteins that are induced to bind GTP when the signal arrives.
• In both cases the proteins gain one or more phosphates in their
activated state and lose the phosphates when the signal decays
• These proteins in turn generally cause the phosphorylation of
downstream proteins as part of a phosphorylation cascade
1. Serine/threonine kinases,
2. Tyrosine kinases
• It is estimated that about 1% of our genes encode protein
kinases and that a single mammalian cell may contain more
than 100 distinct kinds of these enzymes
• Complex cell behaviors, such as survival or proliferation, are
generally stimulated by specific combinations of signals
rather than by a single signal acting alone
• The cell has to integrate the information coming from
separate signals so as to make a proper response to live or
die, or to proliferate or stay quiescent.
• The integration seems to depend on interactions between
the various protein phosphorylation cascades that are
activated by different extracellular signals
SUMMARY
Each cell in a multicellular animal is programmed during
development to respond to a specific set of signals that act in
various combinations to regulate the behavior of the cell and to
determine whether the cell lives or dies and whether it proliferates
or stays quiescent. Most of these signals mediate paracrine
signaling, in which local mediators are rapidly taken up, destroyed,
or immobilized, so that they act only on neighboring cells. In
addition, centralized control is exerted both by endocrine signaling,
in which hormones secreted by endocrine cells are carried in the
blood to target cells throughout the body, and by synaptic signaling,
in which neurotransmitters secreted by nerve cells act locally on the
postsynaptic cells that their axons contact. Cell signaling requires
both extracellular signaling molecules and a complementary set of
receptor proteins in each cell that enable it to bind and respond to
them in a programmed and characteristic way. Some small
hydrophobic signaling molecules, including the steroid and thyroid
hormones and the retinoids, diffuse across the plasma membrane
of the target cell and activate intracellular receptor proteins, which
directly regulate the transcription of specific genes.
Some dissolved gases, such as nitric oxide and carbon monoxide, act as
local mediators by diffusing across the plasma membrane of the target
cell and activating an intracellular enzyme – usually guanylyl cyclase,
which produces cyclic GMP in the target cell. But most extracellular
signaling molecules are hydrophilic and are able to activate receptor
proteins only on the surface of the target cell; these receptors act as
signal transducers, converting the extracellular binding event into
intracellular signals that alter the behavior of the target cell. There are
three main families of cell-surface receptors, each of which transduces
extracellular signals in a different way. Ionchannel- linked receptors are
transmitter-gated ion channels that open or close briefly in response
to the binding of a neurotransmitter. G-protein-linked receptors
indirectly activate or inactivate plasma-membrane-bound enzymes or
ion channels via trimeric GTP-binding proteins (G proteins). Enzymelinked receptors either act directly as enzymes or are associated with
enzymes; the enzymes are usually protein kinases that phosphorylate
specific proteins in the target cell. Through cascades of highly
regulated protein phosphorylations, elaborate sets of interacting
proteins relay most signals from the cell surface to the nucleus,
thereby altering the cell's pattern of gene expression and, as a
consequence, its behavior. Cross-talk between different signaling
cascades enables a cell to integrate information from the multiple
signals that it receives.