It gives the idea about secondary messengers involved in signal transduction. It covers the information of IP3, DAG, Calcium ion and Nitric oxide.

1. Secondary Messengers
IP3,DAG,CA2+ & NO
Presented by: Miss. Rubina U. Watangi. M. Pharm
Department of Pharmacology
Subject: Molecular Pharmacology

2. Contents
1.IP3
 Functions of IP3
 Role in pathophysiology
2.DAG
 Physiological role
3.Calcium ion
 Role of Calmodulin
4.Nitric oxide
 Role of NO

3. IP3
 Inositol triphosphate is a lipid derived secondary messenger
 A product of the hydrolysis of phospholipid
phosphatidylinositol 4,5 biphosphate (PIP2)by the enzyme
phospholipase C

5. FUNCTION of IP3
To transfer a chemical signal received by the cell,
such as from a hormone, neurotransmitters, growth
factors and hypertrophic stimuli such as Ang II
(Angiotensin-II), Beta-adrenergic receptor agonists

6. IP3 ROLE in PATHOPHYSIOLOGY
HUNTINGTON’S DISEASE
 Neurons in the brain degenerate.
 Affects medium spiny neurons (MSN) presents in stratium
 The cytosolic protein Huntingtin (Htt) has an additional 35 glutamine
residues added to its amino terminal region
 This modified form of Htt is called Httexp
 Httexp makes Type 1 IP3 receptors more sensitive to IP3, which leads to
the release of too much Ca2+ from the ER
 The release of Ca2+ from the ER causes an increase in the cytosolic and
mitochondrial concentrations of Ca2+
 The increase in Ca2+ is thought to be the cause of GABAergic MSN
degradation

7. DIACYLGLYCEROL
 Diacylglycerol (DAG) functions as a second messenger signalling lipid
molecule
 Product of the hydrolysis of the phospholipid phosphatidylinositol 4,5-
bisphosphate (PIP2) by the enzyme phospholipase C

8.  DIACYLGLYCEROL
 Diacylglycerol remains within the plasma membrane, activate
serine/threonine protein kinase called protein kinase C(PKC), so named
because it is Ca2+ dependent
 The initial rise in cytosolic Ca2+ induced by IP3 alters the PKC so that it
translocate from the cytosol to the cytoplasmic face to the plasma
membrane.
 There it is activated by the combination of Ca2+, diacylglycerol, and the
phospholipid phosphatidylserine
 Activated PKC phosphorylates target proteins like glucose transporter,
HMG-CoA reductase, cytochromeP450 etc.

9. Physiological role
 Diacylglycerol (DAG) is a lipid signal messenger and plays a
physiological role in β-cells.
 Defective glucose homeostasis increases DAG synthesis,
 DAG may also contribute to β-cell dysfunction in type 2
diabetes.
 The primary function of DAG is to activate protein kinase C
(PKC),

11. CALCIUM IONS
 Acts as a secondary messenger by signal transduction
pathways such as via G protein- coupled receptors.
 Signalling occurs when the cell is stimulated to release
calcium ions (Ca2+) from intracellular stores, or when calcium
enters the cell through plasma membrane ion channels

12. Control of Calcium Levels
 Intracellular calcium levels are controlled by an assortment of
channels, pumps, transporters, buffers, and effector moieties
 Release of calcium from internal stores represents a major
source of signal calcium for many cells.
 The principal calcium stores are the ER, sarcoplasmic
reticulum (SR), Golgi
 Calcium release channels are present on the membranes of
these organelles and gate the flux of calcium from the ER/SR
lumen into the cytosol.

13. Three types of plasma- membrane localized calcium channels :
 Voltage-dependent calcium channels :
 At physiological condition VDCCs are closed (resting
membrane potential)
 The concentration of calcium ions are several times higher
outside of the cell than inside
 Action potential depolarizes plasma membrane, which results
in the opening of VDCCs and calcium ion rush into the cell

14.  Ligand gated calcium channels
 Transmembrane ion channels
 Allow Ca2+ to pass through the membrane in response to
ligand such as neurotransmitter like GABA, acetyl choline
e.g.-
 Nicotinic acetylcholine receptor
 Glutamate / NMDA receptor
 ATP receptor

15.  Stored-operated calcium channels :
 Located in the plasma membrane of all non-excitable cells
(myocytes, endocrine cells etc.)
 They are major sources of intracellular calcium
 Although it was initially considered to function only in non
excitable cells, growing evidence now points towards a central
role for in excitable cells too

17. Calmodulin
 Calmodulin (CaM) (an abbreviation for calcium-modulated
protein)
 It is a multifunctional intermediate calcium-binding
messenger protein expressed in all eukaryotic cells.
 It is an intracellular target of the secondary messenger Ca2+
 The binding of Ca2+ is required for the activation of
calmodulin.
 Once bound to Ca2+, calmodulin acts as part of a calcium
signal transduction pathway by modifying its interactions with
various target proteins such as kinases

18. Calmodulin is Activated by Ca2+ binding undergoes
conformational change that permits Ca2+/calmodulin to bind
targets proteins
A tenfold increase in Ca2+ concentration typically causes a fiftyfold
increase in calmodulin activation
When an activated molecule of Ca2+/calmodulin binds to its target,
Calmodulin further changes its conformation
Whenever the concentration of Ca2+ in the cytosol rises,
Ca2+/calmodulin, activates the plasma membrane Ca2+- pump
uses ATP hydrolysis to pump Ca2+ out of cells or storing it in ER

19. (holo)

20. Role in metabolism
 Calmodulin plays an important role in the activation of
phosphorylase kinase, which ultimately leads to glucose being
cleaved from glycogen by glycogen phosphorylase.
 Calmodulin also plays an important role in lipid metabolism by
affecting Calcitonin.
Role in memory
 Ca2+/calmodulin-dependent protein kinase II (CaMKII) plays a crucial
role in a type of synaptic plasticity called long-term potentiation
(LTP) and requires the presence of calcium/calmodulin.
Role in smooth muscle contraction
 Calmodulin plays an important role in contraction of smooth muscle

21. How calcium controls muscle contraction

23. NITRIC OXIDE
 Gaseous molecule
 NO functions as messenger molecule began with an
accidental observation
 Nitric oxide relaxes the smooth muscles
 Ach binds to receptors on surface of endothelial cells
production and release of an agent diffuses through the cell’s
plasma membrane and causes muscle to relax
 The diffusible agent was identified in 1986 as NITRIC OXIDE
by Louis Ignarro and Salvador Moncada

25. Role of NO
Nitric oxide regulates vascular tone and blood
flow by activating soluble guanylate cyclase (sGC) in
the vascular smooth muscle
 Nitric oxide dilates blood vessels, raising blood
supply and lowering blood pressure.
 Nitric oxide controls mitochondrial Oxygen
consumption by inhibiting Cytochrome C oxidase.