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Secondary messengers.pdf
1. SECONDARY MESSENGERS
Presented by AYUSH ROY
M.Pharm 1st year
Guided by – Dr. Bhrigu K Das
School of Pharmaceutical Science,
GCU, Guwhati
2. CONTENTS
1. Introduction
2. Types of secondary messengers
3. cAMP
4. NO
5. cGMP
6. Inositol 1,4,5- Triphosphate (IP3)
7. Calcium Ion (Ca2+)
8. Diacylglycerol (DAG)
3. ➢ These are components of cell signaling pathways.
➢ Secondary messengers are the intracellular signaling
molecules that transmit signals inside a cell in response to
binding of a primary messenger.
➢ These messengers play an important role in signal
transduction, amplifying and relaying the signal from the cell
surface to various intracellular targets.
➢ Earl Wilbur Sutherland Jr. discovered secondary messengers.
INTRODUCTION
4. TYPES
➢ HYDROPHILIC
➢ HYDROPHOBIC
➢ GASES
a. Diacylglycerol
b. Phosphatidylinositols
a. cAMP
b. cGMP
c. IP3
d. Ca+2
a. NO
b. H2S
c. CO
Membrane - bound
Soluble in aqueous cytoplasm
Can diffuse both through cellular
membranes and aqueous cytosol
5. Cyclic AMP (cAMP)
➢ Cyclic Adenosine Mono Phosphate(cAMP, cyclic AMP, or 3',5'- cyclic adenosine monophosphate)
➢ E.g of primary messengers that cause activation of cAMP release- adrenaline, glucagon
➢ cAMP 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 expression of genes.
6. cAMP Activation
The Ligand binds to the
receptor(GPCR) present in the cell
membrane.
GPCR gets activated and replace
GDP(Guanosine Diphosphate) with
GTP Guanosine Triphosphate)
The α- sub unit dissociates from G
complex and bind to the
effector(Adenyl cyclase)
Adenyl cyclase gets activated and
converts ATP to cAMP in the
presence of Mg2+ as cofactor
7. Functions/Actions of cAMP
I. cAMP is used for intracellular signal transduction, such as transferring
the effects of hormones like glucagon and adrenaline, which cannot pass
through the plasma membrane.
II. In eukaryotic cells , protein kinase A (PKA) is a family of enzymes whose
activity is dependent on levels of cyclic AMP (cAMP). Protein kinase A
has several functions in the cell, including regulation of glycogen, sugar,
and lipid metabolism.
III. In bacteria, the level of cAMP varies depending on the medium used for
growth. cAMP is low when glucose is the carbon source. This occurs
through inhibition of the cAMP- producing enzyme, adenylate cyclase.
The transcription factor cAMP receptor protein (CRP) forms a complex
with cAMP and thereby is activated to bind to DNA. CRP-cAMP
increases expression of a large number of genes, including some encoding
enzymes that can supply energy independent of glucose.
8. NO (Nitric Oxide)
➢ Nitric Oxide is a gaseous signalling molecule. It easily
diffuses across the cell membrane and affect nearby cells
➢ It regulates a wide range of physiologic and
pathophysiologic processes
➢ It is synthesized from arginine and oxygen by the NO
synthase
➢ It is a vasodilator
➢ Inside the cell it interacts and activates soluble guanylyl
cyclase to produce cGMP.
➢ The cGMP then induces muscle relaxation and blood vessels
dilation.
9. Cyclic GMP (cGMP)
➢ Cyclic GMP is synthesized from the nucleotide GTP using
the enzyme guanylyl cyclase.
➢ cGMP serves as the second messenger for
1. Nitric oxide (NO)
2. The response of the rods of the retina to light.
3. Smooth muscle relaxation
➢ 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
10. Inositol 1,4,5-triphosphate(IP3)
➢ Inositol 1,4,5-trisphosphate (IP3) is a molecule that plays a crucial role in cell signaling,
particularly in the regulation of intracellular calcium (Ca2+) levels.
➢ It utilizes G-Proteins in cell signaling mechanism.
➢ The enzyme used in producing this secondary messenger is phospholipase C.
11. Firstly, the first messenger attaches to the G-
Protein Coupled receptor located in the cell’s
plasma membrane and activates it and the
alpha subunit and GTP separates b
The separated α-subunit and GTP complex
moves to the Phospholipase C
This causes the PLC to move away from the
sub-units and bind with PIP2 (phosphatidyl-
inositol-bis-phosphate)
PLC in turn cleaves PIP2 to yield two products
– DAG and IP3.
IP3 then defuses towards the calcium channel
that is imbedded in Endoplasmic Reticulum
membrane
12. The IP3 binds to the channel causing it to change shape and open allowing Ca2+
ions to move from the smooth endoplasmic reticulum into the cytosol.
The ions create cellular responses
When the conc. of Ca2+ ions is greater than cytosol than the ER the IP3 will
disconnect from the channel , therefore closing it.
13. Calcium ion (Ca2+)
➢ Calcium (Ca2+) is an important cellular second messenger for
diverse developmental processes and environmental responses.
➢ Calcium ions once they enter the cytoplasm of a cell they exert
affects on many enzymes & proteins
➢ Low cytosolic Ca2+ at rest (10- 100nM)
➢ Various environmental and developmental processes increases
in cytosolic Ca2+
➢ The concentration of Ca2+ is balanced by the presence of ‘Ca2+
stores’ like vacuoles, endoplasmic reticulum, mitochondria and
cell wall.
14. ➢ Signaling occurs when the cell is stimulated to release Calcium ions from the stores , or when the
calcium enters the cell through plasma membrane ion channels
➢ Sudden increase in the cytoplasmic Ca2+ level up to 500- 1000nM by opening channels in the
endoplasmic reticulum/ plasma membrane.
➢ IP3/DAG pathway stimulates the endoplasmic reticulum Ca2+ ion channels.
➢ Ca2+ acts as a second messenger in two ways:
▪ it binds to an effector molecule, such as an enzyme or proteins, activating it;
▪ it binds to an intermediary cytosolic calcium binding protein such as calmodulin.
➢ The binding of Ca2+causes profound conformational changes in calmodulin that increase
calmodulin`s affinity for its effector molecules.
➢ Calmodulin, when activated, causes contraction of smooth muscles.
15. Diacylglycerol (DAG)
➢ Diacylglycerol (DAG) is a crucial secondary messenger molecule involved in various
intracellular signalling pathways. It plays a significant role in transmitting signals from the
cell surface receptors to various intracellular effectors.
➢ 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, cytochrome P450 etc.
16. Firstly, the first messenger attaches to the G-
Protein Coupled receptor located in the
cell’s plasma membrane and activates it and
the alpha subunit and GTP separates b
The separated α-subunit and GTP complex
moves to the Phospholipase C
This causes the PLC to move away from the
sub-units and bind with PIP2 (phosphatidyl-
inositol-bis-phosphate)
PLC in turn cleaves PIP2 to yield two
products – DAG and IP3.
17. ➢ One of the primary targets of DAG is protein kinase C (PKC), a family of serine/threonine
kinases.
➢ PKC is a key player in signal transduction pathways that regulate cell proliferation,
differentiation, and survival.
➢ Activated PKC translocate from the cytosol to the cell membrane, where it can
phosphorylate a wide range of downstream target proteins
18. REFERENCE
1. Karp, Gerald. Cell and Molecular biology, 6th edition, John Wiley and Sons, Inc.
2. Twyman R.M, Advanced Molecular Biology (2003), Viva Books Private Limited, New Delhi.
3. Berne & Levy - Physiology, 6th Edition
4. Boron & Boulpaep - Medical Physiology, 2nd Edition
5. www.slideshare.net