Celbiologie & Immunologie Samenvatting ‘Essential Cell Biology’ en Hoorcolleges
ESSENTIAL CELL BIOLOGY: CHAPTER 16 – CELL SIGNALING
GENERAL PRINCIPLES OF CELL SIGNALING
Signal transduction is a process in which one type of signal is converted into another type of
signal. In a typical communication between cells, the signalling cell produces a particular type
of extracellular signal molecule that is detected by the target cell. Most animal cells both send
and receive signals, and they can therefore act as both signalling cells and target cells. Target
cells possess proteins called receptors that recognize and respond specifically to the signal
molecule. Signal transduction begins when the receptor on a target cell receives an incoming
extracellular signal and then produces intracellular signalling molecules that alter cell
behaviour.
Signal molecules can be proteins, peptides, amino acids, nucleotides, steroids, fatty acid derivatives, or even dissolved gases. There are
multiple ways of cell signalling:
Endocrine signalling:
Broadcasting the signal throughout the whole body by secreting
it
into the bloodstream or a plant’s sap. Extracellular signal
molecules
used in this way are called hormones and the cells that produce
hormones are called endocrine cells.
Paracrine signalling:
The signal molecules diffuse locally through the extracellular
fluid, remaining in the neighbourhood of the cell that secretes
them. Thus, they act as local mediators on nearby cells.
Autocrine signalling:
Cells respond to the local mediators they themselves produce.
Neuronal signalling:
Like endocrine cells, nerve cells (neurons) can deliver messages
over long distances. In neuronal signalling, a message is not
broadcast widely but is instead delivered quickly and specifically
to individual target cells through private lines. The axon of a neuron terminates at specialized junctions (synapses) on target cells
that can lie far from the neuronal cell body. When activated by signals
from the environment or from other nerve cells, a neuron sends electrical impulses along its axon. On reaching the axon terminal,
these electrical signals are converted into a chemical form, a neurotransmitter. The neurotransmitter then diffuses across the
narrow gap that separates the membrane of the axon terminal from that of the target cell, reaching its destination.
Contact signalling:
It does not require the release of a secreted molecule. Instead, the cells make direct physical contact through signal molecules
lodged in the plasma membrane of the signalling cell and receptor proteins embedded in the plasma membrane of the target cell.
A typical cell in a multicellular organism is exposed to hundreds of different signal molecules in its
environment. Each cell must respond very selectively to this mixture of signals. Whether a cell
responds to a signal molecule depends on whether it possesses a receptor for that signal:
۰ Cell-surface receptors; molecules that are too large or too hydrophilic to cross the plasma
membrane of the target cell rely on receptors on the surface of the target cell to relay their
message across the plasma membrane.
۰ Intracellular receptors; molecules that are small enough or hydrophobic enough to pass
through the plasma membrane and into the cytosol of the target cell, where they bind to
intracellular receptor proteins.
How a cell reacts to a signal depends on the set of
intracellular signalling molecules each cell-surface
receptor produces and how these molecules alter the
activity of effector proteins, which have a direct effect
on the behaviour of the target cell. This system and
the intracellular effector proteins on which it acts vary
from one type of specialized cell to another, so that
different types of cells respond to the same signal in different ways. Thus, the extracellular
signal molecule alone is not the message: the information conveyed by the signal depends
,on how the target cell receives and interprets the signal. A combination of signals can evoke a response that is different from the sum of
the effects that each signal would trigger on its own (tailoring).
The length of time a cell takes to respond to an extracellular signal can vary
greatly, depending on what needs to happen once the message has been received.
Rapid responses are possible because the signal affects the activity of proteins that
are already present inside the target cell, awaiting their marching orders. Slow
responses happen because the response to these extracellular signals requires
changes in gene expression and the production of new proteins.
The signalling pathway:
1. Transmembrane receptors recognize a signal on the outside and relay the
message, in a new form, across the membrane into the interior of the
cell.
2. The message is passed “downstream” from one intracellular signalling
molecule to another, each activating or generating the next signalling
molecule in the pathway, until a metabolic enzyme is kicked into action,
the
cytoskeleton is tweaked into a new configuration, or a gene is switched
on or
off (response of the cell).
The components of these intracellular signalling pathways perform one or more
crucial functions:
1. They can relay the signal onward and thereby help spread it through the cell.
2. They can amplify the signal received, making it stronger, so that a few
extracellular signal molecules are enough to evoke a large intracellular
response.
3. They can detect signals from more than one intracellular signalling pathway
and integrate them before relaying a signal onward.
4. They can distribute the signal to more than one effector protein, creating
branches in the information flow diagram and evoking a complex response.
5. They can modulate the response to the signal by regulating the activity of
components upstream in the signalling pathway, a process known as
feedback.
Feedback regulation can occur anywhere in the signalling pathway and can either
boost or weaken the response to the signal. In positive feedback, a component
that lies downstream in the pathway acts on an earlier component in the same
pathway to enhance the response to the initial signal; in negative feedback, a
downstream component acts to inhibit an earlier component in the pathway to
diminish the response to the initial signal.
Many intracellular signalling proteins behave as molecular switches: receipt of a signal causes them to activate, after which they can
stimulate or suppress other proteins in the signalling pathway. They then persist in an active state until some other process switches
them off again. Thus, for every activation step along the pathway,
there exists an inactivation mechanism. Proteins that act as
molecular switches fall mostly into one of two classes:
Proteins that are activated or inactivated by phosphorylation.
For these molecules, the switch is thrown in one direction by
a protein kinase and in the opposite direction by a protein
phosphatase.
GTP-binding proteins. These toggle between an active and an
inactive state depending on whether they have GTP or GDP
, bound to them. Once activated by GTP binding, many of these proteins have intrinsic GTP-hydrolyzing (GTPase) activity, and they
shut themselves off by hydrolyzing their bound GTP to GDP.
Two main types of GTP-binding proteins participate in intracellular signalling:
۰ Trimeric GTP-binding proteins (G proteins); relay messages from G-protein-coupled
receptors.
۰ Monomeric GTPases; are generally aided by two sets of regulatory proteins that help them
bind and hydrolyze GTP: guanine nucleotide exchange factors (GEFs) activate the switches
by promoting the exchange of GDP for GTP, and GTPase-activating proteins (GAPs) turn
them off by promoting GTP hydrolysis.
Most of the receptors belong to one of three large classes, which differ in the
transduction mechanism they use:
1. Ion-channel-coupled receptors: change the
permeability of the plasma membrane to selected
ions, thereby altering the membrane potential
and, if the conditions are right, producing an
electrical current.
2. G-protein-coupled receptors: activate
membrane-bound, trimeric GTP-binding proteins
(G proteins), which then activate (or inhibit) an
enzyme or an
ion channel in the plasma membrane,
initiating an intracellular signalling cascade.
3. Enzyme-coupled receptors: either act as
enzymes
or associate with enzymes inside the cell.
When stimulated, the enzymes can activate a
wide variety of intracellular signalling
pathways.
Of all the types of cell-surface receptors, ion-channel-coupled
receptors function in the simplest and most direct way. These
receptors are responsible for the rapid transmission of signals
across synapses in the nervous system:
1. When the neurotransmitter binds to ion-channel-coupled
receptors on the surface of a target cell, the receptor alters
its conformation to open a channel in the target cell
membrane, rendering it permeable to specific types of ions,
like Na+, K+, or Ca2+.
2. Driven by their electrochemical gradients, the ions rush into
or out of the cell, creating a change in the membrane
potential.
3. This change in potential may trigger a nerve impulse or make
it easier (or harder) for other neurotransmitters to do so.
G-PROTEIN-COUPLED RECEPTORS
G-protein-coupled receptors (GPCRs) form the largest family of cell surface receptors. These
receptors mediate responses to an enormous diversity of extracellular signal molecules, including
hormones, local mediators, and
neurotransmitters. The signal molecules that
bind GPCRs are as varied in structure as they
are in function: they can be proteins, small
peptides, or derivatives of amino acids or
fatty acids, and for each one of them there is a different receptor or set of
receptors. The GPCR superfamily includes:
Rhodopsin (the light-activated photoreceptor protein in the vertebrate
eye)
The olfactory (smell) receptors in the vertebrate nose
The receptors that participate in the mating rituals of single-celled yeasts.
