secondary messenger
- Created by: Anuja
- Created on: 16-04-12 14:40
Dr Andy Grant
Wolfson CARD
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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