Summary Cell Biology and Immunology

Lecture 1: Cell Signaling & Cell-Cell communication
PART I: Cell Signaling

Cell signaling encompasses:
-​ Cell-cell communication
-​ Sensing and interacting with the extracellular
environment
-​ Sensing and responding to changes in the
intracellular environment

A)​ Contact-dependent
-​ Short distance
-​ Direct cell-to-cell contact
-​ Important in embryonic
development and
immune responses
B)​ Paracrine
-​ Short distance (without
contact)
-​ Secreted signal
molecules
-​ Modulate response in
nearby cells
-​ Important in inflammation
response
C)​ Synaptic
-​ Long distance
-​ Fast (action potential
travels with 100m/s)
-​ Neurotransmitters
-​ Regulated exocytosis into the synaptic cleft
D)​ Endocrine
-​ Long range, broad
-​ Signal molecules: hormones
-​ Secretion into the bloodstream
-​ E.g., insulin, adrenaline


Extracellular signal molecules:
-​ Chemical (e.g. nutrient, hormones, odors, DNA/RNA)
-​ Physical cues (e.g.) pressure, temperature, light)

,Cell Surface Receptors → Large, hydrophilic signal molecules
-​ Ion-channels coupled receptors
-​ G-protein coupled receptors (GPCRs)
-​ Enzyme-coupled receptors (e.g. receptor tyrosine kinases)

Intracellular receptors → Small hydrophobic molecules (e.g. steroids, gasses)
-​ Nuclear receptors (directly activating transcription factors)

Not all receptors are localized on the cell surface
Large, hydrophilic signal molecules​ ​ ​ Small, hydrophobic molecules (e.g. steroids, gasses)




The same input can create distinct responses in different cell types
For example: acetylcholine
a)​ Same receptor
i)​ Heart pacemaker cell → decreased rate of firing
ii)​ Salivary gland cell → secretion
b)​ Different receptor
i)​ Skeletal muscle → contraction

Signaling networks are often highly complex

Signalling responses can be fast or slow
-​ Fast (less than a second to minute) → most likely
altered protein function
-​ Slow (minutes to hours) → Altered gene expression

Breaking large networks down, creates
signaling motifs

Not all receptors are localized on the cell
surface
-​ Large, hydrophilic signal molecules;
cannot cross plasma membrane do
cell surface receptors

, -​ Small, hydrophobic molecules (e.g. steroid, gases); can pass the plasma membrane so
intracellular receptors


Regulation of signaling proteins (molecular switches)
●​ Binding-mediated regulation
○​ Ligand binding
■​ Ion-channel-coupled receptors
■​ G-protein-coupled receptors (GPCRs)
■​ Enzyme-coupled receptors
○​ Protein binding
●​ Enzymatic regulation
○​ GTP hydrolysis (GTP binding proteins)
○​ Post-translational modifications

Ion-channel coupled receptors
●​ Ligands
○​ Neurotransmitters → acetylcholine, glycine,
glutamate, GABA
○​ Second messenger → inositol-1,4,5-triphosphate, Ca2+
●​ Structure
○​ Heterogenous family of multipass
transmembrane proteins
○​ Often with several subunits
●​ Mode of action
○​ Ligand-binding induces opening or closing of the channel
to regulate ion influx / outflux
→ Example: skeletal muscle acetylcholine receptor (motor end
plate, neuromuscular junction)

G-protein-coupled receptors (GPCRs)
●​ Ligands:
○​ Neurotransmitters
○​ Proteins
○​ Peptides
○​ Hormones
○​ Derivatives of amino acids and fatty
acids
●​ Structure
○​ Single polypeptide chain
○​ 7 transmembrane helices
●​ Mode of action
○​ Ligand-binding induces conformational
change in the intracellular domain

, ○​ Associate and regulate the activity of intracellular heterotrimeric G proteins
●​ Importance:
○​ > 35% of all approved pharmaceuticals target GPCRs (including cannabinoids
and opioids)
→ Example: Angiotensin II type 1 - AT1 receptor (mediates constriction of blood vessels)

Enzyme-coupled receptors
●​ Receptor Tyrosine Kinases (RTKs) / Cytokine
receptors
○​ Ligands
■​ Mainly signal protein ligands (e.g.
insulin, growth factors, cytokines)
○​ Structures
■​ Typically single pass membrane domain
■​ Directly encode or are tightly associated with an intracellular kinase
○​ Mode of action
■​ Ligand-binding induces dimerization
■​ Dimerization leads to the inter- and intramolecular phosphorylation of the
receptor
■​ Phosphorylated receptors act as scaffold to recruit additional proteins

Receptor tyrosine kinases (RTKs)​ ​ ​ ​ ​ Cytokine receptor




Binding-mediated regulation
1)​ Ligand binding
a)​ Second messengers: small signaling
molecules release by the cell in response
to receptor activation in order to mediate
the intracellular response
i)​ Hydrophilic second messengers:
(1)​ CA2+, cAMP, cGMP, IP3
ii)​ Hydrophobic second messengers
(1)​ Diacylglycerol, phosphatidylinositol
iii)​ Examples:
→ Ca2+ binds and activated calmodulin
-​ Activated ca2+/Calmodulin-dependent kinase (CamKII,
transcriptional regulation)