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Plasma Membrane, Cell Communication, Signal

Transduction, Nuclear Response, and Gene
Expression
By
Hendra Susanto, S.Pd., M.Kes., Ph.D

Laboratory of Human and Animal Physiology

Department of Biology
State University of Malang
2021

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Excellence in Learning Innovation Structure to Molecular Hierarchy

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Eukaryotic Cells
• Organisms composed of eukaryotic cells are called “eukaryotes”
• Have a membrane bound nucleus which contains the cell’s DNA
• Some eukaryotes are one-celled organisms
• All multicellular organisms are eukaryotes
• Have organelles, each of which is surrounded by (or bound in) a
“plasma membrane”

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Immunofluorescence Staining

Eukaryotic Cytoskeleton: Actin

(red), Microtubules (green)
Surround the Nucleus (blue).
Fluorescence Microscopy.

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Overview: The Cellular Internet
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• Cell-to-cell communication is essential for multicellular

organisms
• Biologists have discovered some universal mechanisms
of cellular regulation

• A signal transduction pathway is a series of steps

by which a signal on a cell’s surface is converted
into a specific cellular response

• Signal transduction pathways convert signals on a

cell’s surface into cellular responses
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Types of Chemical Signaling

Chemical signaling between cells is one of the
most important ways that activities of tissues and
organs are coordinated.
The nervous system is the other major
coordinating system in animals, but even here
chemical signaling is used between adjacent
neurons.

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Modes of cell-cell signaling

1. Direct cell-cell or cell-matrix
2. Indirect: Secreted molecules.
A. Endocrine signaling. The signaling molecules are hormones
secreted by endocrine cells and carried through the circulation
system to act on target cells at distant body sites.
B. Paracrine signaling. The signaling molecules released by one
cell act on neighboring target cells (neurotransmitters).

C. Autocrine signaling. Cells respond to signaling molecules that

they themselves produce (response of the immune system to
foreign antigens, and cancer cells).
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Local and Long-Distance Signaling
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• Cells in a multicellular organisms communicate by chemical messengers

• Animal and plant cells have cell junctions that directly connect the
cytoplasm of adjacent cells
• In local signaling, animal cells may communicate by direct contact
• In many other cases, animal cells communicate using local regulators,
messenger molecules that travel only short distances
• In long-distance signaling, plants and animals use chemicals called
hormones

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 Plasma membranes
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Gap junctions Plasmodesmata

between animal cells between plant cells
Cell junctions

Cell-cell recognition

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Local signaling Long-distance signaling

Target cell Electrical signal Endocrine cell Blood

along nerve cell vessel
triggers release of
neurotransmitter

Neurotransmitter
Secreting Secretory diffuses across
cell vesicle synapse
Hormone travels
in bloodstream
to target cells

Local regulator
diffuses through Target
Target cell
extracellular fluid cell
is stimulated

Paracrine signaling Synaptic signaling

Hormonal signaling

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Some signaling molecules
1. Steroid hormones

This class of molecules diffuse across the plasma membrane and bind to
Receptors in the cytoplasm or nucleus. They are all synthesized from cholesterol.

They include sex steroids (estrogen, progesterone, testosterone) corticosteroids

(glucocorticoids and mineralcorticoids)

Thyroid hormone, vitamin D3, and retinoic acid have different structure and
function but share the same mechanism of action with the other steroids.

Steroid Receptor Superfamily. They are transcription factors that function either
as activators or repressors of transcription.

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2. Nitric oxide (NO) and Carbon Monoxide (CO)

NO, a simple gas, is able to diffuse across the membrane, and alters the
activity of intracellular target enzymes. It’s extremely unstable, so its effects are
local. Ex. It signals the dilation of blood vessels.

3. Neurotransmitters

They signal from neuron to neuron or from neuron to other target cell
(ex. muscle cell ).

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 Excellence in Learning Innovation Steroid Hormones
Steroid hormones are soluble in the plasma membrane and readily enter the
cytosol where they bind to a mobile receptor.

The hormone-receptor complex enters the nucleus and binds to specific genes
where it acts as a transcription factor which turns on the genes.

Messenger RNA is transcribed, leaves the nucleus, and is translated into a

specific protein by ribosomes.

The specific proteins then carry out functions (if they are enzymes) or produce
structures in the target cell.

Because steroid hormones initiate protein synthesis, their effects are produced
more slowly, but are more long-lasting than those produced by other hormones.

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The Three Stages of Cell Signaling

• Earl W. Sutherland discovered how the hormone epinephrine acts
on cells
• Sutherland suggested that cells receiving signals went through three
processes:
• Reception
• Transduction
• Response

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 Excellence in Learning Innovation Three Steps in Cell Signaling
Target organ specificity is the result of specific receptor molecules for the hormone, either on the
plasma membrane surface, or in some cases in the cytoplasm, of cells in the target organ.
1) Reception 2) Transduction 3) Response

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Reception: A signal molecule binds to a receptor

protein, causing it to change shape
• The binding between a signal molecule (ligand) and receptor is highly
specific
• A conformational change in a receptor is often the initial transduction
of the signal
• Most signal receptors are plasma membrane proteins

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Intracellular Receptors
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• Some receptor proteins are intracellular, found in the cytosol or nucleus

of target cells
• Small or hydrophobic chemical messengers can readily cross the
membrane and activate receptors
• Examples of hydrophobic messengers are the steroid and thyroid
hormones of animals
• An activated hormone-receptor complex can act as a transcription
factor, turning on specific genes

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 Hormone EXTRACELLULAR
(testosterone) FLUID The steroid
Excellence in Learning Innovation hormone testosterone
passes through the
plasma membrane.

Plasma
membrane Testosterone binds
Receptor to a receptor protein
protein in the cytoplasm,
Hormone- activating it.
receptor
complex

The hormone-
receptor complex
enters the nucleus
and binds to specific
genes.
DNA

mRNA The bound protein

stimulates the
transcription of
the gene into mRNA.
NUCLEUS New protein

The mRNA is
translated into a
specific protein.
CYTOPLASM

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Receptors in the Plasma Membrane

• Most water-soluble signal molecules bind to specific sites on receptor
proteins in the plasma membrane
• There are three main types of membrane receptors:
• G-protein-linked receptors
• Receptor tyrosine kinases
• Ion channel receptors

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 Excellence in Learning Innovation Signal-binding site

1). a G-protein-linked receptor is a plasma

membrane receptor that works with the help of a
G protein

The G-protein acts as an on/off switch: If GDP is

bound to the G protein, the G protein is inactive
Segment that
interacts with
G proteins
G-protein-linked receptor
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 Signal Signal-binding site
molecule
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a Helix in the Signal
membrane molecule

2) Receptor tyrosine kinases are

membrane receptors that attach Tyrosines
Tyr Tyr
Tyr Tyr Tyr Tyr

phosphates to tyrosines
Tyr Tyr
Tyr Tyr Tyr Tyr
Tyr Tyr
Tyr Tyr Tyr Tyr

A receptor tyrosine kinase can Receptor tyrosine

trigger multiple signal CYTOPLASM

kinase proteins
(inactive monomers)
Dimer

transduction pathways at once

A kinase, alternatively known as Activated relay
a phosphotransferase, is a type proteins

of enzyme that transfers

phosphate groups from high- Cellular

energy donor molecules, such

Tyr Tyr P Tyr Tyr P P Tyr Tyr P response 1
Tyr Tyr P Tyr Tyr P Tyr Tyr P
P
as ATP, to specific substrates. Tyr Tyr
6 ATP 6 ADP
P Tyr Tyr P P Tyr Tyr P Cellular
response 2
The process is referred to as Activated tyrosine- Fully activated receptor
phosphorylation. kinase regions tyrosine-kinase
(unphosphorylated (phosphorylated Inactive
dimer) dimer) relay proteins

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 Signal Gate
closed Ions
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(ligand)

3). An ion channel receptor acts as a gate when the

receptor changes shape Ligand-gated
Plasma

When a signal molecule binds as a ligand to the receptor,

membrane
ion channel receptor

the gate allows specific ions, such as Na+ or Ca2+, through

a channel in the receptor Gate open

Cellular
response

Gate closed

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 Transduction: Cascades of molecular interactions relay signals from
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• Transduction usually involves multiple steps

• Multistep pathways can amplify a signal: A few molecules can
produce a large cellular response
• Multistep pathways provide more opportunities for
coordination and regulation

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Signal Transduction Pathways
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• The molecules that relay a signal from receptor to response are

mostly proteins
• Like falling dominoes, the receptor activates another protein, which
activates another, and so on, until the protein producing the response
is activated
• At each step, the signal is transduced into a different form, usually a
conformational change

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Protein Phosphorylation and Dephosphorylation

• In many pathways, the signal is transmitted by a cascade of protein

phosphorylations
• Phosphatase enzymes remove the phosphates
• This phosphorylation (kinases) and dephosphorylation (phosphotases)
system acts as a molecular switch, turning activities on and off

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 Signal molecule

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Receptor
Activated relay
molecule

Inactive
protein kinase
1 Active
protein
kinase
1
Inactive
protein kinase ATP
2 ADP Active P
protein
PP kinase
Pi 2

Inactive
protein kinase ATP
ADP Active P
3
protein
PP kinase
Pi 3

Inactive
protein ATP
ADP P
Active Cellular
PP protein response
Pi

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Phosphorylation Cascade
Signal transduction pathways often involve an enzyme
phosphorylation cascade.

A series of protein kinases each activate the next in a

series by phosphorylating the inactive precursor.

Because each protein kinase is an enzyme it catalyzes

activation of a number of the inactive kinases of the next
member in the series.
The result is a large amplification of the original signal,
binding of a hormone to the external receptor.

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Small Molecules and Ions as Second Messengers
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• Second messengers are small, nonprotein, water-soluble molecules or

ions
• The extracellular signal molecule that binds to the membrane is a
pathway’s “first messenger”
• Second messengers can readily spread throughout cells by diffusion
• Second messengers participate in pathways initiated by G-protein-
linked receptors and receptor tyrosine kinases

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Cyclic AMP
• Cyclic AMP (cAMP) is one of the most widely used
second messengers
• Adenylyl cyclase, an enzyme in the plasma membrane,
converts ATP to cAMP in response to an extracellular
signal

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Cyclic AMP as a Second Messenger

Most water-soluble hormones do not readily enter the target cell -
they bind to a surface receptor.

In many cases, a G protein is activated which then activates an

enzyme, adenylyl cyclase which converts ATP to cyclic AMP
(cAMP).

cAMP then serves as a second messenger which activates

another enzyme in the cell.

cAMP initiates a chain of events (the signal transduction

pathway) that results in some specific response of the cell to the
first messenger (hormone).

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• Many signal molecules trigger formation of cAMP

• Other components of cAMP pathways are G proteins, G-protein-
linked receptors, and protein kinases
• cAMP usually activates protein kinase A, which phosphorylates
various other proteins
• Further regulation of cell metabolism is provided by G-protein
systems that inhibit adenylyl cyclase

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 First messenger
(signal molecule
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such as epinephrine)
Adenylyl
G protein cyclase

G-protein-linked GTP
receptor

ATP
Second
cAMP messenger

Protein
kinase A

Cellular responses

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Calcium ions and Inositol Triphosphate (IP3)

• Calcium ions (Ca2+) act as a second messenger in

many pathways
• Calcium is an important second messenger because
cells can regulate its concentration

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Excellence in Learning Innovation EXTRACELLULAR
FLUID Plasma
membrane

Ca2+
pump
ATP
Mitochondrion

Nucleus

CYTOSOL

Ca2+
pump
Endoplasmic
reticulum (ER)
ATP Ca2+
pump

Key High [Ca2+] Low [Ca2+]

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• A signal relayed by a signal transduction pathway may trigger an

increase in calcium in the cytosol
• Pathways leading to the release of calcium involve inositol triphosphate
(IP3) and diacylglycerol (DAG) as second messengers

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 EXTRACELLULAR Signal molecule
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FLUID (first messenger)

G protein

DAG
GTP
G-protein-linked PIP2
receptor Phospholipase C
IP3 (second
messenger)

IP3-gated
calcium channel

Various Cellular
Endoplasmic Ca2+ proteins responses
reticulum (ER) activated
Ca2+
(second
CYTOSOL messenger)

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The Central
Excellence Dogma of Molecular Biology~ Biochemistry
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Doerge, R.W. (2002). Nature Reviews Genetics 3, 43-52. doi:10.1038/nrg703

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Central Dogma
DNA code ➔Transcription ➔
Translation ➔ Protein

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Cytoplasmic and Nuclear Responses
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• Ultimately, a signal transduction pathway leads to regulation of one or

more cellular activities
• The response may occur in the cytoplasm or in the nucleus
• Many signaling pathways regulate the synthesis of enzymes or other
proteins, usually by turning genes on or off in the nucleus
• The final activated molecule in the signaling pathway may function as a
transcription factor

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• Many other signaling pathways regulate the synthesis of enzymes or

other proteins, usually by turning genes on or off in the nucleus
• The final activated molecule may function as a transcription factor

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 Reception
Binding of epinephrine to G protein-coupled receptor (1 molecule)
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Transduction
Inactive G protein
Active G protein (102 molecules)

Inactive adenylyl cyclase

Active adenylyl cyclase (102)

ATP
Cyclic AMP (104)

Inactive protein kinase A

Active protein kinase A (104)

Inactive phosphorylase kinase

Active phosphorylase kinase (105)

Inactive glycogen phosphorylase

Active glycogen phosphorylase (106)

Response
Glycogen
Glucose 1-phosphate
(108 molecules)

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Fine-Tuning of the Response

• There are four aspects of fine-tuning to consider
• Amplifying the signal (and thus the response)
• Specificity of the response
• Overall efficiency of response, enhanced by scaffolding
proteins
• Termination of the signal

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Signal Amplification
• Enzyme cascades amplify the cell’s response
• At each step, the number of activated products is
much greater than in the preceding step

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The Specificity of Cell Signaling

• Different kinds of cells have different collections of
proteins
• These differences in proteins give each kind of cell
specificity in detecting and responding to signals
• The response of a cell to a signal depends on the cell’s
particular collection of proteins
• Pathway branching and “cross-talk” further help the
cell coordinate incoming signals

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 Signal
molecule
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Receptor

Relay
molecules

Response 1 Response 2 Response 3

Cell A. Pathway leads Cell B. Pathway branches,

to a single response leading to two responses

Activation
or inhibition

Response 4 Response 5

Cell C. Cross-talk occurs Cell D. Different receptor

between two pathways leads to a different response

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Termination of the Signal

• Inactivation mechanisms are an essential aspect of cell
signaling
• When signal molecules leave the receptor, the
receptor reverts to its inactive state

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Thank You

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