The document discusses secondary messengers including inositol triphosphate (IP3), diacylglycerol (DAG), calcium ions, and nitric oxide (NO) and their roles in cellular signaling and pathophysiology. It highlights how IP3 influences calcium ion release in conditions like Huntington's disease, while DAG activates protein kinase C involved in glucose homeostasis and β-cell dysfunction. Additionally, it explains the multifunctional role of calmodulin in various physiological processes and how nitric oxide regulates vascular tone and blood flow.

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.