Cell Communication

Chapter 9
 Overview

• Overview of cell communication

• Receptor types
• Intracellular receptors
• Signal transduction
– through receptor kinases
– through G-protein coupled receptors

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 Overview of Cell Communication

• Communication between cells requires:

Ligand: the signaling molecule
– Single amino acids, peptides, large proteins, nucleotides, steroids,
dissolved gases (nitric oxide), etc.

Receptor protein: protein molecule to which the ligand binds

– May be on the plasma membrane or within the cell

• The interaction of the ligand with its receptor protein (the

complex) initiates the process of signal transduction which
converts the information in the signal to a cellular response.

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There are four basic mechanisms for cellular communication
depending primarily on the distance between the signaling
and responding cell.
1. Direct contact
2. Paracrine signaling
3. Endocrine signaling
4. Synaptic signaling

Autocrine signaling = cell sends signal to itself!

– immune system; T cells stimulate their own proliferation in response
to a foreign antigen
– development

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Direct Contact
• Molecules on the surface of
one cell are recognized by
receptors on an adjacent cell.
– Early embryonic
development
• Notch signaling
– Highly conserved in
animals
– Important in development
– Notch receptor and its
ligands are transmembrane
proteins; therefore
signaling is restricted to
neighboring cells.
• Cell-to-cell communication e.g.
gap junctions
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Paracrine Signaling
• A signal released
from a cell diffuses
in the extracellular
space and has an
effect on
neighboring cells!
– Short-lived, local
effect
• Early development:
important in
coordinating clusters
of neighboring cells
• Signaling between
immune cells in
vertebrates
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Endocrine Signaling
• Signal enters the
organism’s circulatory
system (blood) and
travels widely
affecting other cells
throughout the body
– Long-lived, distant
effect
• Used extensively by
animals and plants;
e.g. hormones

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Synaptic Signaling
• In animals
• Nerve cells release a
signaling molecule
called neurotransmitter
which binds to
receptors on nearby
cells (another nerve
cell, a muscle, a gland)
• Chemical synapse =
association of nerve
cell and target cell
• Brief effect
• e.g. acetylcholine,
glutamate, GABA
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 Signal Transduction
• When a ligand binds to a receptor protein and forms a
complex, it elicits a response in the target cell.

• Signal transduction: the events within a cell that occur in

response to a signal forming discrete pathways

• Different cell types may respond differently to the same

signal.
– e.g. epinephrine or adrenaline (fight or flight response)
• Different cell types may have the same response to the
same signal.
– e.g. glucagon
• Different cell types can have the same response to different
signals. 11
 Protein Phosphorylation
• A cell’s response to a signal often involves activating or
inactivating proteins.
• Phosphorylation (addition of a phosphate group) is a
common way to change the activity of a protein.
• Protein kinase – an enzyme that adds a phosphate to a
protein
– Phosphate groups are usually added to the three amino acids with
-OH in their R group.
• Serine/threonine kinase class
• Tyrosine kinase class

• Phosphatase – an enzyme that removes a phosphate

from a protein
• A protein can be activated by phosphorylation and
deactivated by dephosphorylation or the reverse.
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Phosphorylation of Proteins

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 Receptor Types
• Receptors can be defined by their location and the type
of ligands they bind.

• Receptors by location:
Intracellular receptors – located within the cell
(cytoplasm); very broad

Cell surface receptor or membrane receptor – located

on the plasma membrane to bind a ligand on the outside of
the cell.
– Transmembrane protein in contact with both the cytoplasm and
the extracellular environment
– Some utilize secondary messengers like cAMP and calcium ions
to relay the message within the cytoplasm.

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 Receptor Types
• Cell surface receptor
or membrane
receptors can be
divided based on their
structure and function
into 3 subclasses:
1. Channel-linked
receptors – ion channel
that opens in response
to the binding of a ligand
2. Enzymatic receptors –
receptor is an enzyme
(almost always a protein
kinase) activated by the
ligand
3. G protein-coupled
receptor – a G-protein
(bound to GTP) assists
in transmitting the signal
from receptor to enzyme

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Channel-linked Receptors/ Chemically-gated Ion
Channels/ Ligand-gated Ion Channels
• Multipass transmembrane protein/protein complex forming a central
pore
• Molecular gates triggered chemically to open and close
– Channel/pore = opens/closes upon activation by ligand binding
• Selective ion channels for one type of ions (Na+, K+, Cl- and Ca2+)
• e.g. Acetylcholine/Na+ channel

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Enzymatic Receptors
• Integral single-pass membrane proteins
• Binds signal extracellularly and catalyzes response intracellularly
• Catalytic region = enzyme OR receptor linked to an enzyme
• Mostly protein kinases

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G-protein Coupled Receptors (GPCR)
• Integral seven-pass transmembrane proteins with cytoplasmic
binding site for G-protein (assistant protein)
• Ligand binding activates the receptor  GTP binds to G-protein,
which translocates to activate an enzyme or ion channel
• e.g. peptide hormones; rod cells in retina

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 Intracellular Receptors
Steroid Hormones
• Small non-polar, lipid-soluble molecules
– May persist for hours in the blood
• Can cross the plasma membrane to bind an
intracellular steroid receptor found in the
cytoplasm
• Usually affect regulation of gene expression
by translocation of the hormone/receptor
complex to the nucleus where they become
known as nuclear receptors.
• e.g. Estrogen, progesterone and testosterone
– Sexual development and behavior
• Others steroid hormones e.g. cortisol
– Various effects: glucose release, anti-inflammatory 19
action
Steroid receptors share structural similarities and are part of
the nuclear receptor superfamily. They have 3 functional
domains:
1. Hormone-binding domain
2. DNA-binding domain
3. Domain that interacts with coactivators to affect gene expression
• An inhibitor blocks the receptor from binding to DNA (by
occupying the DNA-binding site) until the hormone is
present.
• Upon binding of the hormone, the confirmation of receptor
changes, releasing the inhibitor and exposing the DNA-
binding site, thus allowing the receptor to bind specific DNA
nucleotide sequences!
• Activate gene expression (in general)
– e.g. binding sites for cortisol/receptor complex on genes involved in
glucose synthesis
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• Target cell’s response to a lipid-soluble cell signal may vary
enormously, depending on the nature of the cell.
• Even the same type of cells may have different responses
depending on coactivators present.
• Intracellular receptors act in concert with coactivators.
• The number and nature of coactivators differs form cell to
cell; hence the response of the cell to a signal differs as well.
• Estrogen has different effects in different tissues.
• Regulation is not by presence or absence of receptor;
instead, regulation is by presence or absence of coactivator.
• Uterine tissue = coactivator is present = gene expression is
activated = uterus ready for pregnancy
• Mammary tissue = coactivator is lacking = interaction of complex
with another protein = reduced gene expression

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Intracellular Receptors as Enzymes
• Intracellular receptors may act as enzymes.

• Nitric oxide (NO) is a small gas molecule that can diffuse in and out
of cells.

• NO binds to guanylyl cyclase, enabling it to catalyze the synthesis of

cyclic guanosine monophosphate (cGMP).

• cGMP is an intracellular messenger molecule that relaxes smooth

muscle cells.

• Viagra (sildenafil) binds to and inhibits cGMP phosphodiesterase in

penis  cGMP levels high  smooth muscle relaxation in erectile
tissue  increasing blood flow

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Review: Intracellular Receptors

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 Signal Transduction Through Receptor Kinases
• Protein kinases phosphorylate proteins to alter protein function.

Receptor Tyrosine Kinases or RTK

• Membrane receptors possessing
– Single transmembrane domain anchoring the receptor to the membrane
– Extracellular ligand-binding domain
– Intracellular kinase domain (catalytic site; acts as protein kinase)
• When bound by a ligand, the receptor is activated by dimerization
and autophosphorylation.
• Activated receptor adds a phosphate to tyrosine on a response
protein.
• Effect dependent on response proteins

• RTKs may bind hormones or growth factors. e.g. the insulin

receptor, epidermal growth factor receptor (EGF)
• RTKs influence all aspects of the cell including cell cycle, cell
migration, cell metabolism, and cell proliferation.
• Some cancer causing genes code for RTK receptors.
• Plants possess serine-threonine kinases (similar overall structure
and function) named plant receptor kinases. 25
Activation of Receptor Tyrosine Kinase (RTK)

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The Insulin Receptor
• Insulin binds to RTK.
• Activated receptor has
phosphorylated sites that allow
docking.
• Insulin response protein binds to the
phosphorylated receptor and is itself
phosphorylated.
• Signal is transmitted downstream to
lower blood sugar level.

Insulin receptor activates other proteins

which inhibit the synthesis of enzymes
involved in glucose synthesis and
increases the number of glucose
transporter proteins in the plasma
membrane of target cells.

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 Signal Transduction by RTK
Kinase cascade or phosphorylation
cascade
• A series of protein kinases that
phosphorylate each other in succession
• Amplifies the original signal Ras = linker protein;
– A few signal molecules can elicit a large Small GTP-binding
response. protein
– Kinases at each step may affect multiple
substrates.
Mitogen-activated protein (MAP) kinases
– Mitogens stimulate cell division.
• Important class of cytoplasmic kinases
• Activated by kinase cascades
• Induce phosphorylation of transcription
factors that consequently activate gene
expression
– e.g. FGF (Fibroblast Growth Factor) and EGF
(Epidermal Growth Factor) signaling
• Inactivation of RTKs can be done by
dephosphorylation or internalization
(endocytosis of receptor into vesicles;
degraded or recycled)! 28
 MAP Kinase Signal Amplification
Activator = Ras = linker
protein (links RTK and
MAP Kinase)

Adaptor protein
• Acts as linker
between the phospho-
tyrosines of the
receptor and proteins
that initiate
downstream signaling
events
• e.g. Adaptor protein
that activates Ras
• Ras links RTK to the
MAP kinase cascade.
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 Ras
• Small GTP-binding protein (G-
protein)
• Ras has intrinsic GTPase activity
and is mutated in many cancers,
indicative of its central role in
linking growth factor receptors to
their cellular response.
• Ras is active when bound to GTP
and inactive when bound to GDP.
• Ras switch is flipped by
exchanging GDP for GTP via
guanine nucleotide exchange
factors (GEFs) and by Ras
hydrolyzing GTP to GDP.
• Activated Ras activates the first
kinase in the MAP kinase
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cascade.
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 Scaffold Proteins

• Scaffold proteins organize the

components of a kinase cascade
into a single protein complex, the
ultimate in a signaling module
• Binds to each individual kinase
such that they are spatially
organized for optimal function
• More efficient / segregation of
signaling modules
– e.g. Ste5, scaffold protein in yeast =
mating behavior
• Disadvantage: reducing
amplification effect since each
kinase can only affect the
downstream molecule
 Signal Transduction Through G-Protein Coupled
Receptors or GPCRs
G-protein-coupled receptor (GPCRs) – receptors bound to G
proteins
• Largest category of receptor types in animal cells
– More than 750 genes coding for such receptors in humans
• Receptors act by coupling with G-protein
• G-protein – protein bound to GTP(active) (or GDP; inactive)
• G protein provides link between receptor that receives
signal and effector protein that produces cellular response.
• G-protein is a switch turned on by the receptor thus
activating an effector protein which is usually an enzyme
(protein kinase)
• G-protein coupled to GPCR are heterotrimeric G-proteins
– Three subunits (αβγ) 33
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 Signal transduction by GPCRs
• Once activated, the effector protein produces a second messenger
which generates the cellular response to the original signal.
• The effector protein adenylyl cyclase produces cAMP as a second
messenger.
– cAMP binds to and activates the enzyme protein kinase A (PKA).
– PKA adds phosphates to specific proteins.

• The effector protein phospholipase C produces inositol

triphosphate (IP3) and DAG as a second messengers.
– Cleaves PIP2 (phosphatidyl inositol 4,5-bisphosphate) into IP3 plus
DAG.
• Other second messengers include calcium ions (Ca2+).
Cyclic Nuleotides, IP3 and DAG as Second Messengers
Calcium as Second Messenger
cAMP Signaling Pathway

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 IP3 and Calcium Signaling

• Ca2+ initiates some cellular

responses by binding to the
versatile cytoplasmic protein
calmodulin.
• Calmodulin can bind to a
range of proteins including
kinases, ion channels, and
receptor proteins.
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Calcium and Calcium-binding Proteins

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• Different receptors may produce the same second
messenger(s) by acting on the same signal transduction
pathway(s), hence elicit the same cellular response =
convergence of signals
– Glucagon and epinephrine signaling in liver cells = mobilize glucose
• Different isoforms or subtypes of the same receptor can
activate different G-proteins and thereby lead to the
activation of different signal transduction pathways.
– Receptor for epinephrine has 9 isoforms encoded by different genes.
– Sequences are similar but differ in their cytoplasmic domains.
– Different isoforms activate different G proteins leading to different
signal transduction pathways!
Heart = cAMP synthesis = contraction
Gut= cAMP inhibition = relaxation
• GPCRs and RTKs can activate the same signaling
pathways (e.g. MAP kinase or phospholipase C), hence the
existence of crosstalk between the network of
interconnected signaling pathways inside the cell.
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Review: Cell Surface Receptors

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