Second messengers are small intracellular molecules that amplify signals received at cell surface receptors and help transmit them to target molecules inside the cell. The document discusses four main classes of second messengers - cyclic nucleotides, membrane lipid derivatives, calcium ions, and gases like nitric oxide. It provides details on several important second messengers, including cAMP, cGMP, IP3, DAG, and calcium ions, and how they mediate intracellular signaling pathways and cellular responses.
GPCRs are the most dynamic and most abundant all the receptors. The G protein-coupled receptor (GPCR) superfamily comprises the largest and most diverse group of proteins in mammals. GPCRs are responsible for every aspect of human biology from vision, taste, sense of smell, sympathetic and parasympathetic nervous functions, metabolism, and immune regulation to reproduction. GPCRs interact with a number of ligands ranging from photons, ions, amino acids, odorants, pheromones, eicosanoids, neurotransmitters, peptides, proteins, and hormones.
Nevertheless, for the majority of GPCRs, the identity of their natural ligands is still unknown, hence remain orphan receptors.
The simple dogma that underpins much of our current understanding of GPCRs, namely,
one GPCR gene− one GPCR protein− one functional GPCR− one G protein −one response
is showing distinct signs of wear.
Cell cycle and Regulation
* cell Division is occur in every human but these have certaint check point to preventing from the forming the defective cell or cancerious cell.
GPCRs are the most dynamic and most abundant all the receptors. The G protein-coupled receptor (GPCR) superfamily comprises the largest and most diverse group of proteins in mammals. GPCRs are responsible for every aspect of human biology from vision, taste, sense of smell, sympathetic and parasympathetic nervous functions, metabolism, and immune regulation to reproduction. GPCRs interact with a number of ligands ranging from photons, ions, amino acids, odorants, pheromones, eicosanoids, neurotransmitters, peptides, proteins, and hormones.
Nevertheless, for the majority of GPCRs, the identity of their natural ligands is still unknown, hence remain orphan receptors.
The simple dogma that underpins much of our current understanding of GPCRs, namely,
one GPCR gene− one GPCR protein− one functional GPCR− one G protein −one response
is showing distinct signs of wear.
Cell cycle and Regulation
* cell Division is occur in every human but these have certaint check point to preventing from the forming the defective cell or cancerious cell.
This Slide gives you a idea about the subject Cellular and Molecular pharmacology where the cell signalling, secondary messengers and its intracellular signalling pathways has been celarly explained
Cell signaling / Signal Transduction / Transmembrane signaling.
It is the process by which cells communicate with their environment and respond to external stimuli.
When a signaling molecule(ligand) binds to its receptor, it alters the shape or activity of the receptor, triggering a change inside of the cell such as alteration in the activity of a gene / cell division. Thus the original Intercellular Signal is converted into an Intracellular Signal that triggers as a response.
1.What are 2nd messengers Give specific examples. How are they used.pdfwailesalekzydelore94
1.What are 2nd messengers? Give specific examples. How are they used un signal transduction?
2.Signal transduction by RTK signaling pathways
3.Explainhow RTK are activated and inactivated
4.Explainhow signaling pathway mutants are used to dissect the functions of signaling molecul
Solution
1).
Receptors are the protienious structures that act as “signal transducing molecules.” There are
three kinds of membrane receptors namely, ligand gated receptors, G-protein coupled receptors
and kinase linked receptors.
Primary messengers receive the stimulus information from the external environment and passes
into the cell. If the primary messenger cannot pass through the cell membrane, receptors use
second messenger for communication between the receptor and intracellular environment.
Secondary messengers relay the signal information from the receptor-ligand complex, to the
interior of the cell.
G-protein coupled receptors are also known as heptahelical (seven transmembrane-spanning)
receptors. They are connected to the intracellular system through G-protein molecules that
activate secondary messengers.
The three important secondary messengers are cAMP (cyclic adenosine monophosphate), IP3
(ionositol 1,4,5-triphosphate), and DAG (diacyl glycerol).
Adenylate cyclase is an enzyme that converts ATP (adenosine tri phosphate) into cAMP. cAMP
is one of the important secondary messengers of G-protein receptors. Phopholipase C is an
enzyme that hydrolyses phosphatidylinositol bisphosphate (PIP2) into two second messengers
namely, ionositol 1,4,5-triphosphate (IP3) and diacylglycerol (DAG).
Adenylate cyclase is an enzyme that converts ATP (adenosine tri phosphate) into cAMP. cAMP
is one of the important secondary messengers of G-protein receptors. Phospholipase C is an
enzyme that hydrolyzes phosphatidylinositol bisphosphate (PIP2) into two-second messengers
namely, inositol 1,4,5-triphosphate (IP3) and diacylglycerol (DAG).
IP3 increases the calcium release from endoplasmic reticulum by acting through IP3 receptors.
DAG diffuses through the plasma membrane and activates protein kinase C. PKC is present in
many isoforms, which is activated by raised intracellular calcium levels .
Calcium activates calmodulin protein by allosteric binding and thus activates calcium-
calmodulin dependent kinases. The calcium-calmodulin complex activates the myosin light chain
kinases by phosphorylation, which causes muscle contraction.
In contrast, the cAMP acts through Gs type of GPCRs, IP3 acts through Gq type of GPCRs. The
secondary effector in cAMP pathway is PKA (protein kinase A), the secondary effector in IP3
and Calcium-mediated pathways is PKC and calmodulin (calcium directly acts on calmodulin)..
Signal transducing machinery as targets for potential drugs.
Drugs:-
a). Diclofenac- for treating cholera toxin
b). Fasentin- for treating insulin signalling
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2. INTRODUCTION
Second messengers are molecules that relay signals
from receptors on the cell surface to target molecules
inside the cell.
They greatly amplify the strength of the signal, cause
some kind of change in the activity of the cell.
They are a component of cell signaling pathways.
Earl Wilbur Sutherland Jr.,
discovered second messengers,
for which he won the 1971
Nobel Prize.
3. SECOND MESSENGERS
Short lived intracellular signaling molecules
Elevated concentration of second messenger leads to
rapid alteration in the activity of one or more cellular
enzymes
Removal or degradation of second messenger
terminate the cellular response
Four classes of second messengers
Cyclic nucleotides
Membrane lipid derivatives
Ca2+
Nitric oxide/carbon monoxide
5. CYCLIC AMP
cAMP is a second messenger that is synthesized from
ATP by the action of the enzyme adenylyl cyclase.
Binding of the hormone to its receptor activates a G
protein which, in turn, activates adenylyl cyclase.
Leads to appropriate response in the cell by either (or
both):
using Protein Kinase A (PKA) — a cAMP-dependent
protein kinase that phosphorylates target proteins;
cAMP binds to a protein called CREB (cAMP response
element binding protein), and the resultant complex
controls transcription of genes.
Eg.of cAMP action - adrenaline, glucagon, LH
6. 1. The ligand binds to the receptor,
altering its conformation and
increasing its affinity for the G
protein to which it binds.
2. The G subunit releases its GDP,
which is replaced by GTP.
3. The α subunit dissociates from
the G complex and binds to an
effector (in this case adenylyl
cyclase), activating the effector.
4. Activated adenylyl cyclase
produces cAMP.
THE MECHANISM OF RECEPTOR-MEDIATED
ACTIVATION AND INHIBITION OF CAMP
7. 5. The GTPase activity of G
hydrolyzes the bound GTP,
deactivating G.
6. G reassociates with G, reforming
the trimeric G protein, and the
effector ceases its activity.
7. The receptor has been
phosphorylated by a GRK
8. The phosphorylated receptor has
been bound by an arrestin
molecule, which inhibits the
ligand-bound receptor from
activating additional G proteins.
8.
9. GLUCOSE MOBILIZATION: AN EXAMPLE OF A
RESPONSE INDUCED BY CAMP
Binding of hormone
Activation of enzyme and
formation of cAMP.
cAMP binds to PKA &
activates it.
PKA phosphorylates
2 enzymes:
phosphorylates glycogen
phosphorylase- stimulates
glycogen breakdown.
inhibition – prevents
conversion of glucose to
glycogen.
1. Phosphorylase kinase –
2.Glycogen synthetase –
10. CYCLIC GMP
cGMP is synthesized from the nucleotide GTP using the
enzyme guanylyl cyclase.
Nitric oxide stimulates the synthesis of cGMP .
Many cells contain a cGMP-stimulated protein kinase
that contains both catalytic and regulatory subunits.
Some of the effects of cGMP are mediated through
Protein Kinase G (PKG)
cGMP serves as the second messenger for
nitric oxide (NO)
the response of the rods of the retina to light.
11. PHOSPHATIDYLINOSITOL-DERIVED
SECOND MESSENGERS
Phosphatidylinositol ( PI) is a negatively charged
phospholipid and a minor component in eukaryotic cell
membranes.
The inositol can be phosphorylated to form
Phosphatidylinositol-4-phosphate (PIP)
Phosphatidylinositol-4,5-bis-phosphate (PIP2)
Phosphatidylinositol-3,4,5-trisphosphate (PIP3)
Intracellular enzyme phospholipase C
(PLC),hydrolyzes PIP2 which is found in the inner layer
of the plasma membrane. Hydrolysis of PIP2 yields two
products:
Diacylglycerol (DAG)
Inositol-1,4,5-trisphosphate (IP3)
PHOSPHO
INOSITIDES.
12.
13. DIACYLGLYCEROL
Diacylglycerol stimulates protein kinase C activity by
greatly increasing the affinity of the enzyme for calcium
ions.
Protein kinase C phosphorylates specific serine and
threonine residues in target proteins.
Known target proteins include calmodulin, the glucose
transporter, HMG-CoA reductase, cytochrome P450 etc.
14. INOSITOL TRIPHOSPHATE, 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.
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.
15. MODE OF ACTION
Peptide and protein hormones like vasopressin, TSH, and
neurotransmitters like GABA bind to GPCRs
This activate the intracellular enzyme phospholipase C
(PLC).
PLC in turn cleaves PIP2 to yield two products – DAG and
IP3.
Both of these products act as second messengers.
So, the cleavage of PIP2 by PLC is the functional equivalent
of the synthesis of cAMP by adenylyl cyclase.
17. CALCIUM IONS
Many cells respond to extracellular stimuli by altering
their intracellular calcium concentration.
Ca++ acts as a second messenger in two ways:
it binds to an effector molecule, such as an enzyme,
activating it;
it binds to an intermediary cytosolic calcium binding
protein such as calmodulin.
The binding of Ca++ causes profound conformational
changes in calmodulin that increase calmodulin`s
affinity for its effector molecules.
Calmodulin, when activated, causes contraction of
smooth muscles.
18. NITRIC OXIDE
Nitric oxide (NO) acts as a second messenger because
it is a free radical that can diffuse through the
plasma membrane and affect nearby cells.
It is synthesised from arginine and oxygen by the NO
synthase.
It activates soluble guanylyl cyclase, which when
activated produces another second messenger, cGMP.
It is toxic in high concentrations , but is the cause of
many other functions like relaxation of blood vessels,
apoptosis etc.
19. RECENT DEVELOPMENTS
Feng-Yen Li, a student of PhD in biomedical sciences at
UCSF, discovered a "second-messenger" role for
magnesium in T cell signalling, by studying a family
of two boys who suffer from chronic Epstein-Barr virus
infections.
A new Second Messenger, c-di-AMP was
discovered in Staphylococcus aureus with a Role in
Controlling Cell Size and Envelope Stress. This work was
published in the September 2011 Issue of PLoS
Pathogens.
20. CONCLUSION
Signal transduction pathways allow cells to respond
to environmental signals.
In these pathways, a signal is amplified.
This signal amplification is brought about by second
messengers like c AMP, ,c GMP, Ca ions, IP3, DAG and
NO.
Second messengers essentially serve as chemical
relays from the plasma membrane to the cytoplasm,
thus carrying out intracellular signal transduction.
21. REFERENCES
Karp, Gerald. Cell and Molecular biology, 6th edition, John
Wiley and Sons, Inc.
Rastogi S.C, Cell and Molecular biology, 3rd edition (2010),
New Age International (P) Limited, publishers.
Twyman R.M, Advanced Molecular Biology (2003), Viva
Books Private Limited, New Delhi.
http://users.rcn.com/jkimball.ma.ultranet/BiologyPages/
S/Second_messengers.html
http://en.wikipedia.org/wiki/Second_messenger_system