NERVE SIGNALLING
Nerve signalling is a specialized form of cell signalling in which neurons transmit
information through electrical signals within the cell and chemical signals between cells.
At chemical synapses, many neurotransmitters act through G-protein coupled receptors
(GPCRs), which mediate slow but amplified responses via second messengers.
Nerve cell signaling via G protein-coupled receptors (GPCRs) involves neurotransmitters
binding to these membrane receptors, triggering conformational changes that activate
intracellular heterotrimeric G proteins (α, β, γ subunits), leading to the release of second
messengers like cAMP, IP3, or Ca²⁺, which modulate ion channels, enzymes, and ultimately
control neuronal excitability, neurotransmitter release, and synaptic plasticity
(learning/memory). GPCRs are crucial for diverse functions like vision, smell, taste, and
modulating fast-acting neurotransmission, working through pathways like adenylyl cyclase
(Gs/Gi) or phospholipase C (Gq).
Key features
Extremely rapid signalling
High specificity
Uses ion channels, receptors, second messengers
Falls under juxtacrine + paracrine signalling
Types of Nerve Signalling
A. Electrical Signalling (Within Neuron)
Occurs via action potentials
Uses voltage-gated ion channels
Fast, all-or-none response
B. Chemical Signalling (Between Neurons)
Occurs at chemical synapses
Uses neurotransmitters
Slower but highly regulated
Electrical and Chemical Phases of Nerve Signalling
Electrical signalling: Action potential propagates along the axon via voltage-gated
Na⁺ and K⁺ channels.
Chemical signalling: At synapses, neurotransmitters are released and bind to
postsynaptic receptors, including GPCRs.
GPCRs in Neuronal Signalling
GPCRs are seven-transmembrane receptors located on the postsynaptic membrane. Upon
neurotransmitter binding:
1. GPCR undergoes conformational change
2. Heterotrimeric G-protein is activated
3. GDP is exchanged for GTP on the α-subunit
4. α-subunit dissociates to activate effector enzymes
A second messenger is an intracellular signalling molecule produced after a ligand binds to
a cell surface receptor. It amplifies the signal and activates downstream cellular responses.
Examples: cAMP, IP₃, DAG, Ca²⁺
cAMP Second Messenger Pathway
Neurotransmitter binding activates Gs protein
Gs stimulates adenylyl cyclase
ATP is converted to cAMP
cAMP activates Protein Kinase A (PKA)
PKA phosphorylates ion channels and transcription factors such as CREB
Outcome: Increased neuronal excitability and long-term changes in gene expression.
IP₃–DAG Second Messenger Pathway
Neurotransmitter binding activates Gq protein
Gq stimulates phospholipase C (PLC)
PLC cleaves PIP₂ into IP₃ and DAG
IP₃ releases Ca²⁺ from ER
DAG activates Protein Kinase C (PKC)
Outcome: Ca²⁺-dependent modulation of synaptic strength and neurotransmitter release.
Q. Describe the role of second messengers in synaptic transmission and neuronal
plasticity.
Second messengers are intracellular molecules generated upon receptor activation that
amplify extracellular signals. In nerve signalling, second messengers play a crucial role in
synaptic transmission.
Generation of Second Messengers at Synapse
At chemical synapses, neurotransmitters bind to GPCRs, leading to activation of effector
enzymes such as adenylyl cyclase and phospholipase C. This results in the formation of
second messengers like cAMP, IP₃, DAG, and Ca²⁺.
Major Second Messenger Pathways
1. cAMP pathway
Activates PKA
Modulates ion channel conductance
Activates CREB transcription factor
2. IP₃–DAG pathway
IP₃ releases Ca²⁺ from ER
DAG activates PKC
Ca²⁺ acts as a universal second messenger
Feature cAMP Pathway IP₃–DAG Pathway
G-protein Gs / Gi Gq
Effector enzyme Adenylyl cyclase Phospholipase C
Second cAMP IP₃, DAG, Ca²⁺
messengers
Protein kinase PKA PKC
Main function Signal amplification, gene regulation Ca²⁺-dependent
responses
EMBRYONIC CELL DEVELOPMENT
Embryonic cell development refers to the process by which a single fertilized egg (zygote)
undergoes cell division, differentiation, and pattern formation to form a complete
organism.
These processes are entirely regulated by cell signalling pathways that control:
Cell fate determination
Axis formation
Tissue patterning
Organogenesis
Cell signalling regulates:
Gene expression
Cell polarity
Proliferation vs differentiation
Programmed cell death (apoptosis)
FGF Signalling Pathway
It is one of the cell signalling pathway that occurs during embryogenesis.
Type: Paracrine
Role:
Mesoderm induction
Organ development
Mechanism:
Receptor tyrosine kinase (RTK)
Activates MAPK pathway
Fibroblast Growth Factor (FGF) signalling is a key cell signalling pathway that regulates
embryonic cell proliferation, differentiation, and organ development. It plays a crucial
role in early embryogenesis, germ layer formation, and organogenesis by controlling gene
expression in developing cells.
FGF signalling is an essential paracrine signalling pathway.
2. Signalling Molecule and Receptor
Ligand (Signal):
Fibroblast Growth Factors (FGFs)
Protein signalling molecules secreted by embryonic cells
Receptor:
FGF Receptor (FGFR)
A Receptor Tyrosine Kinase (RTK)
Located on the cell membrane
Unlike GPCRs, FGFR directly activates intracellular signalling cascades through
phosphorylation.
4. Mechanism of FGF Signalling
1. FGF binds to FGFR on the target cell
2. Two FGFR molecules dimerize
3. Receptor undergoes autophosphorylation on tyrosine residues
4. Adaptor proteins are recruited
5. MAPK (Ras–Raf–MEK–ERK) pathway is activated
6. Activated ERK enters the nucleus
7. Developmental genes are switched ON or OFF
MAPK PATHWAY (Mitogen-Activated Protein Kinase Pathway)
Unlike GPCRs, MAPK pathway usually starts with:
Receptor Tyrosine Kinase (RTK)
Steps:
1. Ligand (e.g., FGF) binds RTK
2. RTKs dimerize
3. RTKs autophosphorylate on tyrosine residues
📌 These phosphorylated sites act as docking platforms for signalling proteins.
5. The Core MAPK Cascade
This is a three-tier kinase cascade:
Ras → Raf → MEK → ERK
Step 1: Ras Activation (Signal Switch)
Ras is a small GTP-binding protein
Exists in two states:
o Inactive: Ras-GDP
o Active: Ras-GTP
How Ras is activated:
Adaptor proteins (Grb2, SOS) help exchange GDP → GTP
Ras becomes ON
📌 Key idea: Ras is the molecular ON/OFF switch
Step 2: Raf Activation (MAPKKK)
Active Ras activates Raf
Raf is a MAP kinase kinase kinase (MAPKKK)
📌 Raf phosphorylates the next kinase
Step 3: MEK Activation (MAPKK)
Raf phosphorylates MEK
MEK = MAP kinase kinase
📌 MEK is special because it phosphorylates both:
Serine
Threonine residues
Step 4: ERK Activation (MAPK)
MEK phosphorylates ERK
ERK = Extracellular signal-regulated kinase
📌 ERK is the final effector kinase
6. ERK Enters the Nucleus (Very Important)
Once activated:
ERK moves from cytoplasm → nucleus
ERK phosphorylates:
o Transcription factors
➡ This leads to:
Gene expression
Protein synthesis
Cell fate decisions
7. Signal Amplification (Why MAPK Is Powerful)
One ligand →
activates many RTKs →
activates many Ras →
activates many Raf →
activates many ERK molecules
📌 Result:
A small signal produces a large biological response
Ligand → RTK → Ras → Raf → MEK → ERK → Nucleus → Gene expression
Therefore, the MAPK pathway is a central signalling cascade that transmits extracellular
signals to the nucleus through a series of protein kinases, thereby regulating gene expression,
cell proliferation, differentiation, and embryonic development.
FGF signalling regulates embryonic gene expression through activation of the MAPK
pathway.
FGF signalling is involved in:
Mesoderm induction
Cell proliferation
Limb development
Brain and neural development
Organogenesis
FGF signalling is a crucial developmental signalling pathway that acts through receptor
tyrosine kinases to regulate cell proliferation, differentiation, and organ formation during
embryogenesis. Thus, FGF signalling plays a central role in coordinating embryonic growth
and development.