second messenger system ( molecular endocrinology)

1. Second messenger system
Submitted by:
Ankumoni Dutta
M.Sc 3rd sem.
Roll no-7

2. Introduction
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. Second
messengers serve to greatly amplify the strength of the
signal.

3. History
• Earl Wilbur Sutherland, Jr., discovered second messengers, for
which he won the 1971 Nobel Prize in Physiology or Medicine.
• Sutherland saw that epinephrine would stimulate the liver to
convert glycogen to glucose (sugar) in liver cells, but
epinephrine alone would not convert glycogen to glucose.
• He found that epinephrine had to trigger a second messenger,
cyclic AMP, for the liver to convert glycogen to glucose.
• The mechanisms were worked out in detail by Martin Rodbell
and Alfred G. Gilman, who won the 1994 Nobel prize.

4. Second messenger systems
There are three major class of second messenger
systems:
• Adenylyl Cyclase–cAMP Second Messenger System.
• The Cell Membrane Phospholipid Second Messenger
System.
• Calcium-Calmodulin Second Messenger System

5. Adenylyl Cyclase–cAMP Second
Messenger System
• Some of the hormones that achieve their effects through cAMP as a
second messenger: adrenaline, glucagon , luteinizing hormone (LH).
• Binding of the hormone to its receptor activates
• a G protein which, in turn, activates adenylyl cyclase.
• The resulting rise in cAMP turns on the appropriate response in the
cell by either (or both):
– changing the molecular activities in the cytosol, often using
Protein Kinase A (PKA) — a cAMP-dependent protein kinase
that phosphorylates target proteins;
– turning on a new pattern of gene transcription.

7. Cyclic GMP (cGMP)
• Cyclic GMP is synthesized from the
nucleotide GTP using the enzyme
guanylyl cyclase. Cyclic GMP serves
as the second messenger for :
• atrial natriuretic peptide (ANP)
• nitric oxide (NO)
• the response of the rods of the retina to
light.
• Some of the effects of cGMP are
mediated through Protein Kinase G
(PKG) — a cGMP-dependent protein
kinase that phosphorylates target
proteins in the cell

8. The Cell Membrane Phospholipid Second Messenger System.
• 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).
• it hydrolyzes phospholipids — specifically phosphatidylinositol-
4,5-bisphosphate (PIP2) which is found in the inner layer of the
plasma membrane.
• Hydrolysis of PIP2 yields two products: Inositol trisphosphate
(IP3) and diacylglycerol (DAG)

9. ….contd
• 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. The lipid portion of DAG is arachidonic acid, which is the
precursor for the prostaglandins and other local hormones that cause
multiple effects in tissues throughout the body.
• Inositol-1,4,5-trisphosphate (IP3) This soluble molecule diffuses
through the cytosol and binds to receptors on the endoplasmic
reticulum causing the release of calcium ions (Ca2+) into the cytosol.
calcium ions then have their own second messenger effects, such as
smooth muscle contraction and changes in cell secretion.

11. Calcium-Calmodulin Second Messenger System
This second messenger system operates in response to the entry
of calcium into the cells.
Normally, the level of calcium in the cell is very low (~100 nM).
There are two main depots of Ca2+ for the cell:
• The extracellular fluid (ECF — made from blood), where the
concentration is ~ 2 mM or 20,000 times higher than in the
cytosol;
• the endoplasmic reticulum ("sarcoplasmic" reticulum in
skeletal muscle).

12. ….contd
In response to many different signals, a rise in the concentration of Ca2+
in the cytosol triggers many types of events such as
• muscle contraction;
• exocytosis, e.g.,
– release of neurotransmitters at synapses.
– 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)
• apoptosis
• a variety of biochemical changes mediated by Protein Kinase C (PKC).

13. …contd
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.

16. …..contd
Getting Ca2+ into (and out of) the cytosol:
• Voltage-gated channels open in response to a change in membrane
potential, e.g. the depolarization of an action potential;
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.

17. ….contd
• Receptor-operated channels
These are found in the post-synaptic membrane and open
when they bind the neurotransmitter. Example: NMDA
receptors.
• G-protein-coupled receptors (GPCRs). These are not
channels but they trigger a release of Ca2+ from the
endoplasmic reticulum. They are activated by various
hormones and neurotransmitters (as well as bitter
substances on taste cells in the tongue

18. …..contd
• On entering a cell, calcium ions bind with the protein
calmodulin.
• The calmodulin changes its shape and initiates multiple
effects inside the cell, including activation or inhibition of
protein kinases.
• Activation of calmodulin-dependent protein kinases
causes, via phosphorylation, activation or inhibition of
proteins involved in the cell’s response to the hormone.

19. ….contd
• The normal calcium ion concentration in most cells of the
body is 10-8 to 10-7mol/L, which is not enough to activate
the calmodulin system. But when the calcium ion
concentration rises to 10-6 to 10-5 mol/L, enough binding
occurs to cause all the intracellular actions of calmodulin.
• This is almost exactly the same amount of calcium ion
change that is required in skeletal muscle to activate
troponin C, which causes skeletal muscle contraction.

20. Reference
 Guyton and Hall, text book of medical physiology, eleventh
edition; Pg: 912- 915
 Second messenger system - Wikipedia, the free
encyclopedia.html
 Second Messenger Systems at the US National Library of
Medicine Medical Subject Headings (MeSH)