Cell Signaling
“Principles”
Dr. Fridoon Jawad Ahmad
HEC Foreign Professor
King Edward Medical University
Visiting Professor LUMS-SSE
2nd Biggest Leap
2.5 billion Years
Multicellular = Specialization = Coordination
Ability to sense & respond to external and internal
environment
Why Signaling System
In order to survive even simplest organisms need to
sense and respond to their environment.
It is critical that the cells of multicellular organisms
communicate to coordinate their efforts (Running).
Cells in a multicellular organism are specialized and
rely on each other for the support (brain sugar).
During development there have to be checks
balances on differentiation (analogy society).
Signals
Can
Instruct
Cells to
Perform
Various
functions
(Manipulating
Gene
expression)
Design
1) Ligand binding
2) Conformational change
Cytoplasmic domain
3) Mediators
4) Cell function modified
Expression of One Gene Can Alter
Phenotype of Cells
Modes
Low Affinity
Receptors & Cell Machinery
Receptor combinations confer cell
behavior in an environment
flooded with hundreds of ligands
Cellular machinery specifies cell
response to a particular ligand
High Turnover (NO)
Ach
NO
Receptor-ACh
NO synthase
Deamination
Diffusion
G-cyclase
cGMP
Relaxation
NO half life 5 seconds
Receptors: Intracellular (ICR)
Small Hydrophobic Lipid soluble
molecules eg steroid & thyroid
hormones, retinoids & Vit D etc
Blood transport via carrier
proteins longer life (thy days
Ach ms) Carrier left outside
Inactive ICR may be DNA bound
or in cytoplasm (NLS nonfunctional)
Activated receptor binds DNA
induces gene transcription
ICR Specificity
Different cells with identical ICRs regulate different
genes due to other cell specific mediators
Right combination of co-activators/gene regulators
required to transcribe specific genes (testosterone)
ICR Transcription
Ligand binding removes inhibitory proteins and
facilitates binding of transcription activators
Cell-Surface Receptors (CSR)
CSR Response Time
Neurotransmitters produce all or noting response
Small IC
Mediators
SICMs are produced/released
in response to signal received
by the receptor
SICMs donot have an
enzymatic activity of their
own however they modify the
function of other molecules
IC Proteins
1
3
6
4&5
7
2
1 Relay proteins simply pass the message to the
next signaling component in the chain.
2 Messenger proteins carry the signal from one part
of the cell to another, such as from the cytosol to the
nucleus.
3 Adaptor proteins link one signaling protein to
another, without themselves conveying a signal.
4 Amplifier proteins, which are usually either
enzymes or ion channels, greatly increase the signal
they receive, either by producing large amounts of
small intracellular mediators or by activating large
numbers of downstream intracellular signaling
proteins. When there are multiple amplification steps
in a relay chain, the chain is often referred to as a
signaling cascade.
5 Transducer proteins convert the signal into a
different form. The enzyme that makes cyclic AMP is
an example: it both converts the signal and amplifies
it, thus acting as both a transducer and an amplifier.
6 Bifurcation proteins spread the signal from one
signaling pathway to another.
7 Integrator proteins receive signals from two or
more signaling pathways and integrate them before
relaying a signal onward.
8 Latent gene regulatory proteins are activated at the
cell surface by activated receptors and then migrate
to the nucleus to stimulate gene transcription.
Signaling in E. coli
After ligand binding
change in tertiary
structure of extra cellular
part of EnvZ leads to
structural change in its
cytoplasmic domain
making it a kinase (auto..).
EnvZ-P can now phosphorilate OmpR (responder)
outside signal in and
amplified.
Signaling in E. coli
Receptor conformational change
after ligand binding which activates
kinase activity.
Phosphorilation alters responder
function.
Signal amplified.
Transcription factor activated.
Protein synthesis results in altered
cell activity.
G Protein-Linked Receptors
Ligand binding causes a structural change
permitting G protein to bind receptor.
Binding of G protein to activated receptor causes it
to exchange GDP for GTP (receptor releases ligand).
G Protein-Linked Receptors
Subunit of G protein separates and activates an
effector molecule (causing a functional change).
Epinephrine effects different cells differently (heart
muscle contracts, intestinal vascular smooth muscle
relaxes more nutrients absorbed (Adnl C inhibition).
Second Messenger
Second messengers are allosteric regulators and do
not have enzymatic activity
Cyclic AMP (cAMP) can bind ion
channels to open them or bind
enzymes to exposing their active sites.
Enzyme Activation
Via Second
messenger
The cAMP-dependent protein kinases (PKA) are
tetramers, consisting of two regulatory (R) subunits and
two catalytic (C) subunits.
In the tetrameric form PKA is enzymatically inactive.
Binding of cAMP to the R subunits causes dissociation
of the two C subunits, which then can phosphorylate
specific acceptor proteins.
cAMP-dependent protein kinase (cAPK), glycogen phosphorylase
kinase (GPK), and glycogen phosphorylase (GP) — are all
regulated, directly or indirectly, by cAMP by phosphoprotein
phosphatase, which removes the phosphate residues from the
inactive form of glycogen synthase At high cAMP levels, cAPK
phosphorylates an inhibitor of phosphoprotein phosphatase (PP)
CRE
Gs vs Gi
PKC Activation
via Gq
Cell type
Organ/system
Activators
ligands --> Gq-GPCRs
Effects
smooth muscle cell (gastrointestinal
tract sphincters)
digestive system
•prostaglandin F2α[4] -->
•thromboxanes[4]
contraction
•smooth muscle cells in:iris dilator
muscle (sensory system)
•urethral sphincter (urinary system)
•uterus (reproductive system)
•arrector pili muscles(integumentary system)
•ureter (urinary system)
•urinary bladder (urinary system)[5][6]
Various
•adrenergic agonists --> α1 receptor
contraction
•smooth muscle cells in:iris constrictor muscle
•ciliary muscle
sensory system
acetylcholine --> M3 receptor
contraction
smooth muscle cell (vascular)
circulatory system
•5-HT --> 5-HT2A receptor
•adrenergic agonists --> α1 receptor
•vasoconstriction[7][8]
smooth muscle cell (seminal tract[9])
reproductive system
•adrenergic agonists --> α1 receptor
ejaculation
smooth muscle cell (GI tract)
digestive system
•5-HT --> 5-HT2A or 5-HT2B receptor[7]
•acetylcholine (ACh) --> M3 receptor
•contraction[10]
smooth muscle cell (bronchi)
respiratory system
•5-HT --> 5-HT2A receptor
•adrenergic agonists --> α1 receptor
•acetylcholine --> M3[11] andM1 receptor[12]
bronchoconstriction[7]
proximal convoluted tubule cell
kidney
•angiotensin II --> AT1 receptor
•adrenergic agonists --> α1 receptor
•stimulate NHE3 --> H+ secretion &
Na+ reabsorption[13]
•stimulate basolateral Na-K ATPase -->
Na+ reabsorption[13]
neurons in autonomic ganglia
nervous system
acetylcholine --> M1 receptor
EPSP
neurons in CNS
nervous system
•5-HT --> 5-HT2A receptor
•acetylcholine --> M1 receptor
•neuronal excitation (5-HT)[7]
•memory? (acetylcholine)[14]
platelets
circulatory system
5-HT --> 5-HT2A receptor[7]
aggregation[7]
ependymal cells (choroid plexus)
ventricular system
5-HT --> 5-HT2C
receptor[7]
heart muscle
circulatory system
•adrenergic agonists --> α1 receptor
positive ionotropic effect[5]
serous cells (salivary gland)
digestive system
•acetylcholine --> M1 andM3 receptors
•adrenergic agonists --> α1 receptor
•↑secretion[5]
•increase salivary potassium levels.
serous cells (lacrimal gland)
digestive system
•acetylcholine --> M3 receptor
•↑secretion[8]
adipocyte
digestive system/endocrine system
•adrenergic agonists --> α1 receptor
•glycogenolysis andgluconeogenesis[5]
hepatocyte
digestive system
•adrenergic agonists --> α1 receptor
•glycogenolysis andgluconeogenesis[5]
sweat gland cells
integumentary system
•adrenergic agonists --> α1 receptor
•↑secretion[5]
parietal cells
digestive system
acetylcholine --> M1 receptors[12]
↑ gastric acid secretion
↑cerebrospinal fluid secretion[7]
Receptor Tyrosine Kinases & Ras
Autophosphorylation
Activated RTKs Indirectly Bind
and Activate RAS
RAS Helpers
Protein Kinase Cascade
Signal Amplification
Ras Experiment
Alternate
Names
Comparison