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M 114
Second messenger in the hormone action
Second Messengers
Second messengers are molecules that relay signals received at receptors on the cell surface such as the
arrival of protein hormones, growth factors, etc. to target molecules in the cytosol and/or nucleus.
But in addition to their job as relay molecules, second messengers serve to greatly amplify the strength of
the signal. Binding of a ligand to a single receptor at the cell surface may end up causing massive changes in
the biochemical activities within the cell.
There are 3 major classes of second messengers:
Cyclic Nucleotides
adrenaline
glucagon
luteinizing hormone (LH)
Cyclic AMP is synthesized from ATP by the action of the enzyme adenylyl cyclase.
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Inositol trisphosphate (IP3) and diacylglycerol (DAG)
Peptide and protein hormones like
vasopressin,
thyroid-stimulating hormone (TSH), and
angiotensin
and neurotransmitters like GABA
bind to G protein-coupled receptors (GPCRs) that activate the intracellular enzyme phospholipase C
(PLC).
diacylglycerol (DAG)
DAG remains in the inner layer of the plasma membrane. It recruits Protein Kinase C (PKC) a
calcium-dependent kinase that phosphorylates many other proteins that bring about the changes in
the cell.
As its name suggests, activation of PKC requires calcium ions. These are made available by the
action of the other second messenger IP3.
inositol-1,4,5-trisphosphate (IP3)
o This soluble molecule diffuses through the cytosol and
o binds to receptors on the endoplasmic reticulum causing
o the release of calcium ions (Ca2+) into the cytosol.
o The rise in intracellular calcium triggers the response.
Example: the calcium rise is needed for NF-AT (the "nuclear factor of activated T cells") to
turn on the appropriate genes in the nucleus. [Discussion]
The remarkable ability of FK506 and cyclosporine to prevent graft rejection is due to their
blocking this pathway.
The binding of an antigen to its receptor on a B cell (the BCR) also generates the second messengers DAG
and IP3.
muscle contraction;
exocytosis, e.g.,
o release of neurotransmitters at synapses (and essential for the long-term synaptic changes that
produce Long-Term Potentiation (LTP) and Long-Term Depression (LTD);
o secretion of hormones like insulin
activation of T cells and B cells when they bind antigen with their antigen receptors (TCRs and
BCRs respectively)
adhesion of cells to the extracellular matrix (ECM)
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apoptosis
a variety of biochemical changes mediated by Protein Kinase C (PKC).
Normally, the level of calcium in the cell is very low (<0.0001 mM). There are two main depots of Ca2+ for
the cell:
The extracellular fluid (ECF made from blood), where the concentration is ~ 48 mg/ml (1.2 mM
or >10,000 times higher than in the cytosol;
the endoplasmic reticulum ("sarcoplasmic" reticulum in skeletal muscle).
However, its level in the cell can rise dramatically
when channels in the plasma membrane open to allow it in from the extracellular fluid or
from depots within the cell such as the endoplasmic reticulum and mitochondria.
Voltage-gated channels
o open in response to a change in membrane potential, e.g. the depolarization of an action
potential;
o are found in excitable cells:
skeletal muscle
smooth muscle (These are the channels blocked by drugs, such as felodipine
[Plendil], used to treat high blood pressure. The influx of Ca2+ contracts the smooth
muscle walls of the arterioles, raising blood pressure. The drugs block this.)
neurons. When the action potential reaches the presynaptic terminal, the influx of Ca2+
triggers the release of the neurotransmitter.
the taste cells that respond to salt [Link].
o allow some 106 ions to flow in each second following the steep concentration gradient.
Receptor-operated channels
These are found in the post-synaptic membrane and open when they bind a neurotransmitter.
G-protein-coupled receptors (GPCRs). These are not channels but they trigger a release of Ca2+ from
the endoplasmic reticulum as described above. They are activated by various hormones and
neurotransmitters (as well as bitter substances on taste cells in the tongue Link).
Ca ions are returned
2+
How can such a simple ion like Ca2+ regulate so many different processes? Some factors at work:
localization within the cell (e.g., released at one spot the T-system is an example or spread
throughout the cell)
by the amount released (amplitude modulation, "AM")
by releasing it in pulses of different frequencies (frequency modulation, "FM")
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