SECONDARY MESSENGER

SYSTEM

Preceptor :Dr. Manorama SwainDr. Manorama SwainAssociate ProfessorDepartment of Biochemistry

Presenter :Aditya AgarwalAditya Agarwal2nd YearM.B.B.S.

S.C.B. Medical CollegeS.C.B. Medical CollegeCuttackCuttack

Sir Earl Wilbur Sutherland Jr.Sir Earl Wilbur Sutherland Jr.( 1915 – 1974 )( 1915 – 1974 )

The Man behind it : The Man behind it : Nobel Nobel Prize Prize 19711971

4

Signal Transmission

ContentsContents

What are Second Messengers ?

Why Secondary Messenger Systems ?

Usage of S.M. Systems

1

2

3

5 Different S.M. Systems

What are Second Messengers ?What are Second Messengers ?

They are small, intra-cellular molecules that transmit signals from a receptor to a target.

They are short-lived.

They can have multiple downstream targets, thereby expanding the scope of signal transmission. [Signal Amplification]

Their concentration inside the cell is in accordance with the biochemical message sent by the ligand bound to receptor.

Signal TransmissionSignal Transmission

ReceptionReception

TransductionTransduction

InductionInduction

G-G-proteinprotein

EffectorEffectorEnzymeEnzyme

WHY Secondary Messenger System ?WHY Secondary Messenger System ?

Direct Gene Activation Signal Transduction Faster, Short-term

Slower, Long-term

Steroidal

Non-Steroidal

Cascade

Mechanism

Usage of Second MessengersUsage of Second Messengers

Second Messengers

Hormones

cAMP Epinephrine, Norepinephrine, FSH, LH, TSH, ADH, Glucagon, Calcitonin and

Parathormone

Protein Kinase Insulin, Prolactin, GH, Oxytocin, Erythropoietin and other Growth Factors

Ca2+ and/or Phosphoinositol

Epinephrine, Norepinephrine, Angiotensin II, ADH, GnRH and TRH

cGMP Atrial Natriuretic Peptide and Nitric Oxide

Note : Not only do Multiple Hormones utilize the same SM system, Note : Not only do Multiple Hormones utilize the same SM system, but a single hormone can activate more than one SM system too. but a single hormone can activate more than one SM system too.

Cyclic AMP SystemCyclic AMP System

Cyclic AMP SystemCyclic AMP System

Activation of G-Protein

Cyclic AMP SystemCyclic AMP System

Adenylyl Cyclase

cAMP Phosphodiesterase

PPi

H2O

H+

ATP

cAMP

AMP

Synthesis

Breakdown

Cyclic AMP SystemCyclic AMP System

Protein Kinase A(inactive)

Protein Kinase A(active)

Cytoplasmic Nuclear

Phosphorylation of other enzymes

Activates CREB (Transcription Factor) which binds to cAMP Response Element

(DNA Sequences)

TRANSCRIPTION

CREB -CREB -cAMP cAMP

Response Response Element Element

Binding ProteinBinding Protein

Cyclic AMP SystemCyclic AMP System

Functions of Protein Kinase A :

1. Stimulates Glycogenolysis & Gluconeogenesis

2. Sequesters Ca2+ into Sarcoplasmic Reticulum

3. Activates Reward System in CNS

4. Vasodilation for Smooth Muscles

Did you know ?

CAFFEINE & THEOPHYLLINE

inhibit cAMP PDE

Cyclic GMP SystemCyclic GMP System

Cyclic GMP SystemCyclic GMP System

Functions of Protein Kinase G :

1. Vasodilation i.e., Increased Blood Flow

2. Regulates Na+ Ion Channel Conductance

3. Photo-transduction in the Eye

4. Penile Erection

Did you know ?

SILDENAFIL inhibits PDE 5

IPIP33 and DAG System and DAG System

Functions of Protein Kinase C

1. Vasoconstriction

2. Smooth Muscle Contraction in GIT & RT

3. Platelet aggregation

4. Ejaculation

Did you know ?

CYCLOSPORINE (Immuno-suppressive) blocks this pathway

!

IPIP33 and DAG System and DAG System

Receptor Tyrosine KinaseReceptor Tyrosine Kinase

Tyrosine Kinase SystemTyrosine Kinase SystemLigand

Receptor Tyrosine Kinase

Ligand-Receptor Complex

Phosphorylation of other

enzymes

Phosphorylation of

cytosolic Tyrosine Kinase

Phosphorylation of

Transcription Factors

Gene Transcripti

on & Translatio

n

Receptor-mediated

Endocytosis

Physiological

Effects

JAK-STAT

Pathway

Tyrosine Kinase SystemTyrosine Kinase System

When Growth factors receptors remains in “ON”

state, then the cell undergoes uncontrolled

mitosis (CANCER)…

IMATINIB Mesylate in

the treatment

of CML.

HERCEPTIN used for Breast Cancer.

DEFITINIB used for

Lung Cancer.

SUNITINIBused for

GIST.

SummarySummary

Take Home/Hostel MessageTake Home/Hostel Message

Shift in treatment from Radiotherapy to Chemotherapy because of high specificity of Tyrosine Kinase inhibitors (TKI).

1. What are Second Messengers

2. Different SM Systems

3. Functions of Protein Kinases

4. Principles behind usage of Coffee, Tea, Viagra, Immuno-suppressives and Anti-Cancer Drugs

Now that Mechanism of Action of various Protein Kinase Receptors been delineated, a lot of research is being done on Drugs blocking these receptors.

BibliographyBibliography

1. Dr. Manorama Swain

2. Lehninger’s Principles of Biochemistry

3. Guyton’s Textbook of Physiology

4. http://en.wikipedia.org

5. http://www.britannica.com

6. http://www.ncbi.nlm.nih.gov (USA National Library of Medicine)