Concept 11.3: Transduction: Cascades of molecular interactions relay signals from receptors to target molecules in the cell Flashcards
The binding of a specific signaling molecule to a receptor in the plasma membrane triggers the first step in the signal transduction pathway—
the chain of molecular interactions that leads to a particular response within the cell.
the signal-activated receptor activates another molecule, which activates yet another molecule, and so on, until the protein that produces the
final cellular response is activated.
The molecules that relay a signal from receptor to response, which we call relay molecules in this book, are often
proteins.
Keep in mind that the original signaling molecule is not physically passed along a signaling pathway; in most cases, it never even
enters the cell.
At each step, the signal is transduced into a different form, commonly a
shape change in the next protein.
Very often, the shape change is brought about by
phosphorylation.
. An enzyme that transfers phosphate groups from ATP to a protein is generally known as a
protein kinase
Recall that a receptor tyrosine kinase is a specific kind of protein kinase that phosphorylates tyrosines on the other receptor tyrosine kinase in a
dimer.
Most cytoplasmic protein kinases, however, act on proteins different from
themselves.
Another distinction is that most cytoplasmic protein kinases phosphorylate either of two other
amino acids, serine or threonine, rather than tyrosine.
Serine/threonine kinases are widely involved in signaling pathways in
animals, plants, and fungi.
Many of the relay molecules in signal transduction pathways are
protein kinases, and they often act on other protein kinases in the pathway
The sequence of steps shown in the figure is similar to many known pathways, including those triggered in yeast by mating factors and in animal cells by many growth factors.
phosphorylation cascade
The signal is transmitted by a cascade of protein phosphorylations, each causing a
shape change in the phosphorylated protein.
The shape change results from the interaction of the newly added phosphate groups with
charged or polar amino acids on the protein being phosphorylated
The shape change in turn alters the function of the
protein, most often activating it
In some cases, though, phosphorylation instead
decreases the activity of the protein.
About 2% of our own genes are thought to code for
protein kinases, a significant percentage.
A single cell may have hundreds of different kinds, each specific for a different
substrate protein.
Together, protein kinases probably regulate the activity of a
large proportion of the thousands of proteins in a cell.
Among these are most of the proteins that, in turn,
regulate cell division.
Abnormal activity of such a kinase can cause
abnormal cell division and contribute to the development of cancer.
Equally important in the phosphorylation cascade are the _____________________, enzymes that can rapidly remove phosphate groups from proteins, a process called
protein phosphatases, dephosphorylation
By dephosphorylating and thus inactivating protein kinases, phosphatases provide the mechanism for
turning off the signal transduction pathway when the initial signal is no longer present.
Phosphatases also make the protein kinases available for reuse, enabling the cell to respond again to an
extracellular signal.
The phosphorylation-dephosphorylation system acts as a molecular switch in the cell, turning activities
on or off, or up or down, as required.
At any given moment, the activity of a protein regulated by phosphorylation depends on the
balance in the cell between active kinase molecules and active phosphatase molecules.
Not all components of signal transduction pathways are
proteins.
Many signaling pathways also involve small, nonprotein, water-soluble molecules or ions called
second messengers
The pathway’s “first messenger” is considered to be the
extracellular signaling molecule—the ligand—that binds to the membrane receptor
Because second messengers are
small and also water-soluble, they can readily spread throughout the cell by diffusion.
For example, as we’ll see shortly, a second messenger called ___________ carries the signal initiated by epinephrine from the plasma membrane of a liver or muscle cell into the cell’s interior, where the signal eventually brings about glycogen breakdown.
cyclic AMP
Second messengers participate in pathways that are initiated by both
G protein-coupled receptors and receptor tyrosine kinases.
The two most widely used second messengers are
cyclic AMP and calcium ions, Ca2+ .
A large variety of relay proteins are sensitive to
changes in the cytosolic concentration of one or the other of these second messengers.
Earl Sutherland established that,
without passing through the plasma membrane, epinephrine somehow causes glycogen breakdown within cells.
This discovery prompted him to search for a
second messenger that transmits the signal from the plasma membrane to the metabolic machinery in the cytoplasm.
Sutherland found that the binding of epinephrine to the plasma membrane of a liver cell elevates the cytosolic concentration of
cyclic AMP (cAMP; cyclic adenosine monophosphate)
an enzyme embedded in the plasma membrane, __________________________________, converts ATP to cAMP in response to an extracellular signal—in this case, provided by epinephrine.
adenylyl cyclase (also known as adenylate cyclase)
But epinephrine doesn’t stimulate
adenylyl cyclase directly.
When epinephrine outside the cell binds to a G protein-coupled receptor, the protein activates adenylyl cyclase, which in turn can catalyze the
synthesis of many molecules of cAMP.
In this way, the normal cellular concentration of cAMP can be boosted
20-fold in a matter of seconds.
The cAMP broadcasts the signal to the
cytoplasm.
It does not persist for long in the absence of the hormone because a different enzyme,
called phosphodiesterase, converts cAMP to AMP.
Another surge of epinephrine is needed to boost the
cytosolic concentration of cAMP again.
Subsequent research has revealed that epinephrine and many other signaling molecules lead to activation of
adenylyl cyclase by G proteins and formation of cAMP
The immediate effect of an elevation in cAMP levels is usually the activation of a serine/threonine kinase called
protein kinase A.
The activated protein kinase A then phosphorylates various other proteins, depending on the
cell type.
Further regulation of cell metabolism is provided by other G protein systems that inhibit
adenylyl cyclase
In these systems, a different signaling molecule activates a different receptor, which in turn activates an inhibitory
G protein that blocks activation of adenylyl cyclase.
People acquire the cholera bacterium, ______________ by drinking contaminated water.
Vibrio cholerae,
The bacteria form a biofilm on the lining of the
small intestine and produce a toxin
The cholera toxin is an enzyme that chemically modifies a
G protein involved in regulating salt and water secretion.
Because the modified G protein is unable to hydrolyze GTP to GDP, it remains stuck in its active form, continuously stimulating
adenylyl cyclase to make cAMP
The resulting high concentration of cAMP causes the intestinal cells to secrete large amounts of
salts into the intestines, with water following by osmosis.
An infected person quickly develops
profuse diarrhea and if left untreated can soon die from the loss of water and salts.
In one pathway, a molecule similar to cAMP called _________________ is produced by a muscle cell in response to the gas nitric oxide (NO) after it is released by a neighboring cell.
cyclic GMP (cGMP)
cGMP then acts as a second messenger that causes
relaxation of muscles, such as those in the walls of arteries
A compound that inhibits the hydrolysis of cGMP to GMP, thus prolonging the signal, was originally prescribed for chest pains because it
relaxed blood vessels and increased blood flow to the heart muscle.
Under the trade name___________ this compound is now widely used as a treatment for erectile dysfunction in human males.
Viagra,
Many of the signaling molecules that function in animals—including neurotransmitters, growth factors, and some hormones—induce responses in their target cells via
signal transduction pathways that increase the cytosolic concentration of calcium ions (Ca2+)
is even more widely used than cAMP as a second messenger.
Calcium
Increasing the cytosolic concentration of Ca2+ causes many responses in animal cells, including
muscle cell contraction, exocytosis of molecules (secretion), and cell division.
In plant cells, a wide range of hormonal and environmental stimuli can cause brief increases in cytosolic Ca2+ concentration, triggering various signaling pathways, such as the
pathway for greening in response to light
Cells use Ca2+ as a second messenger in pathways triggered by both
G protein-coupled receptors and receptor tyrosine kinases.
Although cells always contain some Ca2+ , this ion can function as a second messenger because its
concentration in the cytosol is normally much lower than the concentration outside the cell
In fact, the level of Ca2+ in the blood and extracellular fluid of an animal is often more than
10,000 times higher than that in the cytosol
Calcium ions are actively transported out of the cell and are actively imported from the cytosol into the
endoplasmic reticulum (and, under some conditions, into mitochondria and chloroplasts) by various protein pumps.
As a result, the calcium concentration in the ER is usually much higher than that in the
cytosol.
Because the cytosolic calcium level is low, a small change in absolute numbers of ions represents a relatively large percentage change in
calcium concentration.
In response to a signal relayed by a signal transduction pathway, the cytosolic calcium level may rise, usually by a mechanism that releases
Ca2+ from the cell’s ER.
These two messengers are produced by cleavage of a certain kind of phospholipid in the plasma membrane.
inositol trisphosphate (IP3) and diacylglycerol (DAG).
Because IP3 acts before calcium in these pathways, calcium could be considered a
“third messenger.”
