Signal TransductionThe process of converting a signal from outside
the cell to a functional change within the cell
Scott Wilson
Department of Neurobiology
Director Neuroscience Theme Graduate Program
Outline I:
I. Overview cell to cell communication
II. Ligands
III. Receptors
IV. Activation of Intracellular signaling pathways and
production of second messengers
V. Effector Proteins
VI. Mechanisms to terminate signal transduction
Outline II:
I. Neurotrophin signaling- From discover of Neurotrophin
Receptors to their activation of intracellular pathways
Signal Transduction Overview
Cell-Cell Communication and Cell Signaling
Nervous System
Development-Neurons and Glia
Neurons: Synaptic Transmission
Synaptic Plasticity
Glial Cell Function
Two Main Types of Cell-Cell Communication
Direct- Gap Junctions
Indirect- Receptors and Signal Transduction
Cell-Cell Communication-Cell Signaling
Indirect- Signal Transduction
Conversion of one signal (outside the cell-or at the
cell membrane) into another signal (inside the cell)
Purposes:
Relay Internal Metabolic and External
Environmental Information
Generate Behavior-Synaptic Transmission
Integrate and Store Information – Synaptic
Plasticity
Types of Cell-Cell Communication
Defined by:
Where the signal originates
What the signal is released into
Where the target cells are
What types of cells are signaling
Ligands
Types of Ligands:
Hormones
Neurotransmitters
Growth Factors
Trophic Factors
Inflammatory Mediators
Cytokines and Chemokines
Antigens and Antibodies
Developmental Signals
ECM components
Sensory Stimuli- light, mechanical touch, odorants,
pheromones, sound
Signals/Ligands Function by Activating Receptors
Many types of ligands and receptors
Ligands may be
Freely diffusible molecules (either (A) hydrophilic-cell impermeant molecules
or (B) hydrophobic-cell permeant molecules)
Bound to carrier proteins
(C) Tethered (associated with the cell plasma membrane
or extracellular matrix)
Receptors can be located on
cell surface (in plasma
membrane) or inside the cell
(intracellular)
What are Receptors?
Receptors are proteins that mediate a biological change following ligand binding
Ligand + receptor
[Ligand-receptor complex]
Non-covalent Interactions via
Non-covalent interactions
Receptors Properties
Reversibility
A ligand binds to its the receptor through non-covalent interactions
Affinity
How strongly a ligand binds to the receptor- Equilibrium dissociation constant = KD
Efficacy
How well an agonist can activate a receptor once it is bound- refers to response
Specificity = Selectivity
How well a receptor can distinguish among different ligands
Location = Localization
Where is the receptor localized in the cell, on the plasma membrane or in
intracellular vesicles. Where in the plasma membrane-synaptic or extrasynaptic
Two Major Categories of Cellular Receptors
Intracellular Receptors:
Ligand must be hydrophobic and able to
pass directly through plasma membrane
Ex. estrogen
Cell Surface Receptor:
Ligands can be either hydrophilic or
hydrophobic
Receptors: Three Major Types (see next
slides)
Intracellular Receptors
Intracellular Receptor:
Ligand must be
hydrophobic and able to
pass directly through
plasma membrane
Glucocorticoids
Sex steroids
Mineralocorticoids
Thyroid hormones
Retinoids
Three Types of Cell Surface Receptors
Cell Surface Receptors
Three classes defined by mechanism used to transduce ligand-binding into intracellular signaling events.
Many common properties are shared by these three classes of receptors
1. Membrane spanning (integral membrane) proteins that undergo allosteric changes in response to
ligand binding. Their location on the PM is controlled by the secretory and endosomal pathways.
2. Ligand binding site(s) on the outside (extracellular domain) and sites for protein-protein interactions on
inside (cytoplasmic domain).
3. High affinity and selectivity for their ligands.
4. Function via signal transduction, though by very different molecular mechanisms.
5. Can regulate ion channels and therefore affect the membrane potential or excitabilty of neurons.
6. Have mechanisms for signal amplification and desensitization.
7. Are regulated by phosphorylation.
8. Can generate second messengers, and regulate protein kinases and protein phosphorylation.
Cell Surface Receptors Activate Signaling Protein Cascades
Channel or
transporter
altered [ion]
membrane
potential
Figure 15-1 Molecular Biology of the Cell (© Garland Science 2008)
Protein Phosphorylation in Signal
Transduction
Tyrosine Kinases
Serine/Threonine Kinases
How can phosphorylation affect a protein?
Activity: Enzyme, channel,
transporter, CytSk & TF
Protein localization
Protein-protein interactions
Protein degradation
Ion Channel-Coupled Receptors, Channel-Linked Receptors
Ligand-Gated Ion Channels, Ionotropic Receptors
Mediate the Majority of
Synaptic Transmission in the CNS and NMJ
Ionotropic Glutamate, GABA, Ach Receptors
GPCRs in the Nervous System
Ligands-Receptors include:
Norepinephrine (Noradrenergic)
Epinephrine (Adrenergic)
Dopamine
Serotonin
Acetylcholine (Muscarinic)
Glutamate (Metabotropic)
GABA (GABAB)
Adenosine
ATP
Neuropeptides-Som, Enkeph, NPY,
CCK, AngII, Oxy
Sensory stimuli- light, odorants
G Protein-Coupled Receptors-Metabotropic
Diphosphate
Guanine
Triphosphate
Guanosine
Heterotrimeric G Protein
G Protein Coupled Receptors: GPCRs
Largest family of cell surface receptors with >1000 genes (a lot of these are
odorant receptors)
Targets of the majority of therapeutic drugs (over 50% of all prescription
pharmaceuticals on the market)
Core structure: 7 transmembrane -helices (extracellular N-term,
intracellular C-term)
Respond to a massive number and variety of ligands
Divergent ligands –Photons-Retinal; small organic molecules;
neurotransmitters and neuromodulators; glycoproteins; hormones
Use a range of signaling strategies
G Protein-Coupled Receptors Activate Heterotrimeric G Proteins
Neurotransmitter
G-protein
Receptor
intracellular [GTP]/[GDP] = 9/1
GPCRs stimulate exchange of GTP for GDP on G
Four Families of Heterotrimeric G Proteins
G Protein-Coupled Receptor Signaling
Neurotransmitter or Hormone
G-protein
Enzymes
Receptor
Second Messenger
Map Kinase
G Effectors:
Adenylyl cyclase +/PLC
GEFs for small GTPases
Gbg Effectors:
Aden cyclase
PLC
PI3K
GPCR-G Protein Gs Activates Adenylyl Cyclase
* cAMP is a second
messenger
One Major Target of cAMP:
cAMP Dependent Protein Kinase (PKA)
Consensus Sequence
RRXS/TX
Downstream Targets of PKA
PKA regulates CREB and Transcription
HAT
Amplification During Signal Transduction
Amplification
provides extremely high sensitivity:
Only a few molecules bound can
produce a response
Amplification can occur at several steps
Amplification allows for the induction of
responses in cells with low density of
receptors or the induction of responses
at low concentration of signaling
molecules
How is GPCR signaling terminated?
Early
RE
LE
GPCR regulation: desensitization and down-regulation
Enzyme-Linked Receptors
Catalytic Receptors:
Receptor Tyrosine Kinase (RTKs)
Receptor Tyrosine Phosphatase
Receptor Serine/Threonine Kinase
Ligand binding often induces dimerization of receptor which facilitates its activation
Enzyme-Coupled Receptors
Receptors possess either intrinsic catalytic
activity or associate directly with enzymes. All
growth factor and trophic factor receptors and
most cytokine receptors are enzyme linked.
Example: TrkB (BDNF receptor)
Receptors (or their associated proteins) are
catalytic.
Catalytic Receptors:
Receptor Tyrosine Kinases
Receptor Tyrosine Phosphatases
Receptor Serine/Threonine Kinases
Receptor Tyrosine Kinases
RTK Activation and Tyrosine Phosphorylation
RTK activation and Tyrosine Phosphorylation
RTKs can Activate Phospholipase C (g)
PH
Insulin IGF1
EGF PDGF TCR
NGF BDNF
Activation mechanisms for the PLC
PLCg produces
IP3 and DAG
which are second
messengers
RTKs can Activate PI3K
EGF bFGF
NGF Insulin
IGF-1 PDGF
VEGF HGF
BDNF Nrg
PI3Kinase phosphorylates PIP2 to form PIP3 that recruits
and AKT at the cell membrane
RTKs also activate the Small GTPase Ras
Ras
SOS is a GTP exchange
factor for Ras- it activates
Ras
Ras activates the mitogen-activate protein kinase pathway (MAP)
Downstream of Erk Map Kinase
Mechanisms terminate signaling of RTKs
Turnover of RTKs by the ESCRT pathway
Concepts in SD1- Receptors and ligands mediate signal transduction
2- Post-translational modifications (PTM) allow for rapid
changes in protein function
3-Signals can be amplified by the activation of multiple
down stream pathways: ex. cAMP, IP3, PIP3
4-Signal transduction results in a change in cellular
function- ex. Ion channel function, cytoskeletal
organization (cell shape) or gene expression
5- PTM also are required to terminate signaling- ex.
Phosphorylation of phosphatase activates its activity,
ubiquitination of proteins can cause their internalization
