secondary messenger

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  • Created by: Anuja
  • Created on: 16-04-12 14:40

Dr Andy Grant

Wolfson CARD

[email protected]

BL0213

Physiology and Pharmacology of 

the CNS

Secondary Messenger SystemsLearning Objectives

After this lecture, with some further reading, you should be able 

to:

• Understand the fundamental role of 2nd messengers in 

modulating cellular activity

• Describe the association of 3 major receptor classes with 2nd 

messenger function

• Understand the importance of spatial and temporal localisation 

of 2nd messengers to signal specificity

• Give examples of multiple effector enzymes that enable 

different classes of receptor to couple to the same response

• Give examples of different 2nd messengers that converge on a 

common target.What is a second(ary) messenger?

Primary messengers carry signals between cells 

(e.g. neurotransmitters, hormones)

Second messengers carry signals within cells, 

following primary messenger signalingWhy are second messengers important?

Neurotransmitter release

Synaptic plasticity

Neurite outgrowth

Gene expre ion

Ce viabil ty

Proliferation

Synaptogenesis

Nociception

Enzyme regulation

Infla ationMajor themes

Complexity vs. 

speed

Signal amplification

Sensitivity of response

Temporal localisation

Selectivity of response

Spatial localisationMain types of second messengers

• Cyclic nucleotides: 

3’,5’-cyclic adenosine monophosphate (cAMP) 

3’,5’-cyclic guanosine monophosphate (cGMP)

• Molecules derived from lipid bilayers:

Inositol 1,4,5-trisphosphate (IP3

)

Diacylglycerol (DAG)

Arachidonic acid

• Gases:

Nitric oxide (NO)

Carbon monoxide (CO)

• Ions:

Calcium (Ca

2+

)Second messengers are usually 

produced by effector enzymes

Nitric oxide 

synthase

Phospholipase C

Phospholipase A2

Guanylate cyclase

Adenylate cyclase

Effector enzyme

L-arginine NO

IP3

and DAG

Phosphatidylinositol 4,5-

bisphosphate (PIP2

)

Arachidonic 

acid

Phosphatidylcholine

Phosphatidylethanolamine

cGMP

Guanosine-5’-triphosphate 

(GTP)

cAMP

Adenosine-5’-triphosphate 

(ATP)

Substrate Product

2+1. G-protein coupled receptors (GPCRs) 

Gαs

- ↑ cAMP production by adenylate cyclase

Gαi

- ↓ cAMP production by adenylate cyclase

Gαq/11

- ↑ IP3

and DAG production by PLCβ

2. Ligand-gated ion channels

Ca

2+

entry

3. Tyrosine kinase-linked receptors

Phosphorylation cascades activate effector 

enzymes (e.g. PLCγ) and protein kinases

Second messenger activity is associated 

with all 3 classes of transmembrane receptorHow do second messengers modulate 

cellular activity in the nervous system?

• Rapid turnover of second messenger molecules –

transient effects (secs)

• Longer-term responses require covalent modification of 

proteins

• Achieved by  phosphorylation of target proteins (e.g. ion 

channels, transcription factors, enzymes) by protein kinases

• Effects reversed by  dephosphorylation of target proteins 

by phosphatasesModulating protein activity: 

changing shapes

Serine

Tyrosine

ThreonineSerine/Threonine kinases – eg PKC, PKA, PKG, MAPK, CaMK

Receptor Serine/Threonine kinases – eg TGFβ

Dual specificity protein kinases – Tyrosine/Threonine – eg MEKs

Non-receptor tyrosine kinases – eg Src family

Receptor tyrosine kinases – eg neurotrophin receptor

~400 Serine/threonine and dual specificity kinases 

~100 Tyrosine kinases identified to date

Also ~ 50 lipid kinases – e.g. PI-3-kinase

Types of protein kinase

• Initial estimates were for 1-2,000 protein kinases

• Sequence analysis of human genome suggests 518:One ligand, different responses:

Agonists can produce different cellular responses by:

Acting on different surface receptors (e.g. noradrenaline 

contracts smooth muscle via  α1

-adrenoceptors and relaxes 

smooth muscle via β2

-adrenoceptors)

Different actions of the same receptor / second messenger 

(e.g. ACh acts on vascular endothelial cells / smooth muscle 

cells…

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