Signal Transduction

https://www.youtube.com/watch?v=MoHQAyMGCFw

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 INTRODUCTION

• External signals such as odorants,, ions, hormones,

growth factors, and neurotransmitters can all serve as
chemical messengers linking neighboring or distant cells.
• Even external signals that are not considered chemical
in nature (e.g., light and mechanical or thermal stimuli)
may ultimately be transduced into a chemical
messenger.
• The binding of ligand to a receptor protein initiates a
sequence of events in the cell leading to cell’s response
to that messenger and this is called signal transduction.
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 KEY TERMS
• Receptor ; A specific protein in either the plasma
membrane or interior of a target cell with which
a chemical messenger combines.
• For a molecule to act as a signal, it must bind to
a receptor
• In most cases interaction of the ligand (signalling
molecule) with the specific receptor results in
association of the receptor and effector molecule
that initiates a cellular response
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• The combination of a messenger to a receptor causes a
change in the conformation of the receptor (receptor
activation)
• The diverse sequences of events between receptor
activation and cellular responses are signal transduction
pathways
• Signal= receptor activation
• Transduction = process of transforming a stimulus to a
response
• Signal transduction pathways differ between lipid soluble
and water soluble messengers
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 Cont’d
• Agonist ; A chemical messenger that binds to a
receptor and triggers the cell’s response; often
refers to a drug that mimics a normal messenger’s
action.
• Antagonist ; A molecule that competes for a
receptor with a chemical messenger normally
present in the body. The antagonist binds to the
receptor but does not trigger the cell’s response
• Affinity ; The strength with which a chemical
messenger binds to its receptor.
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 Cont’d
• Effectors; enzymes, channels, transport proteins,
contractile elements and transcription factors
• Specificity ; The ability of a receptor to bind only
one type or a limited number of structurally
related types of chemical messengers.
• Saturation The degree to which receptors are
occupied by a messenger. If all are occupied, the
receptors are fully saturated

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 MECHANISMS OF CELLULAR
COMMUNICATION

• Cells can communicate with one another by

chemical signals
• A hormone is a substance that is produced in
one tissue or organ and released into the blood
and carried to other organs (targets), where it
acts to produce a specific response.

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 MODES OF CELL COMMUNICATION
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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 CELLS CAN ALSO COMMUNICATE BY
DIRECT INTERACTIONS . (Intercellular
)
connections )

1. Gap Junctions
• Neighboring cells can be electrically and metabolically coupled
by means of gap junctions formed between apposing cell
membranes.
• Mammalian gap junctions permit the passage of molecules that
are less than ∼1200 Da but restrict the movement of
molecules that are greater than ∼2000 Da
• Gap junctions are also excellent pathways for the fl ow of
electrical current between adjacent cells, playing a critical role
in cardiac and smooth muscle.
• The permeability of gap junctions can be rapidly regulated by
changes in cytosolic concentrations of Ca2+, cAMP, and H+ as
well as by the voltage across the cell membrane or membrane
potential (Vm) 10
Gap Junctions

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 2. TIGHT JUNCTIONS

• Tight junctions (zonula occludens)

• Are the attachments between cells (often
epithelial cells).
• May be an intercellular pathway for solutes,
depending on the size, charge, and
characteristics of the tight junction.
• May be “tight” (impermeable), as in the renal
distal tubule, or “leaky” (permeable), as in the
renal proximal tubule and gallbladder
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 3.Anchoring junctions
• Anchoring junctions are cell junctions that remain
anchored to adjacent cells while being attached
to components of the extracellular matrix.
• Location
• They are commonly found in tissues prone to
constant mechanical stress, e.g., skin and heart.
• Structure and Composition
• Anchoring junctions are composed of several
transmembrane linkers like cadherin and
integrins. They also use intermediate filaments
and actin filaments as the cytoskeletal anchor.
Functions
• They play an essential role in keeping the cells together
and in the structural cohesion of tissues.
• They stabilize the cell’s position, provide stability and
rigidity, and support tissue integrity by holding cells
together.
• These junctions also form a tight seal between
neighboring cells to restrict the flow of molecules
between cells and from one side of the tissue to the
other.
• They also regulate the motility of both single cells and
cellular masses through their substrates.
 Types of anchoring junctions
a. Desmosomes, also (macula adherens)
b. Hemidesmosomes
c. Adherens junctions. ,also (zonula
adherens)
 a.Desmosomes

• Desmosomes are protein attachments between

adjacent cells. It is found only in animal cells.
• Inside the plasma membrane, a desmosome
bears a disk‐shaped structure from which
protein fibers extend into the cytoplasm.
• Some of these proteins extend across the
membrane, while others anchor the junction
within the cell.
 Desmosomes cont,

• Specialized adhesion proteins, called cadherins, are

found on the membranes of both cells and interact in
the space between them, holding the membranes
together.
• Inside the cell, the cadherins attach to a cytoplasmic
plaque, which connects to the intermediate filaments
and helps anchor the junction.
• Desmosomes act like spot welds to hold together
tissues that undergo considerable stress, such as skin or
heart muscle.
• They pin adjacent cells together, ensuring that cells in
organs and tissues that stretch, such as skin and cardiac
muscle, remain connected in an unbroken sheet.
 b) Hemidesmosome

• These structures look similar to the

previous type but are different
functionally and in their content.
• However, unlike desmosomes, their
transmembrane proteins are integrin.
 C.Adhering Junctions

• In adherens junctions, the cytoplasmic actin

filaments act as the cytoskeletal anchor.
• Like desmosomes and hemidesmosomes,
their transmembrane anchors are composed
of cadherins and integrins.
• Cadherins anchor to other cells, and integrins
anchor to the extracellular matrix.
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 General Classes of hormone
1. Amines ; Epinephrine,Norepinephrine,thyroid
hormones(thyroxine and triiodothyronine etc
2. Proteins and peptides; Angiotensin II,Glucagon,
parathyroid, insulin etc
3. Steroids aldosterone,estrogens,progestrone,cortisol
etc
4. Other small molecules; amino acids, nucleotides,
ions (Ca²⁺)gases (nitric oxide)

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 Receptors
• For a molecule to act as a signal, it must bind to a
receptor
• In most cases interaction of the ligand (signalling
molecule) with the specific receptor results in
association of the receptor and effector molecule
that initiates a cellular response
• Effectors; enzymes, channels, transport proteins,
contractile elements and transcription factors

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 Cont.
• Competition ; The ability of different molecules very similar
in structure to combine with the same receptor.
• Down-regulation; A decrease in the total number of
target-cell receptors for a given messenger in response to
chronic high extracellular concentration of the messenger.
• Up-regulation ; An increase in the total number of target-
cell receptors for a given messenger in response to a
chronic low extracellular concentration of the messenger.
• Supersensitivity ; The increased responsiveness of a target
cell to a given messenger, resulting from up-regulation.

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 TYPES OF RECEPTORS
1. Ligand gated ion channels
i. Integral membrane proteins, the hybrid
receptor/channels are involved in signalling between
electrically excitable cells.
ii. Binding of a neurotransmitter like acetylcholine to its
receptors which in fact is part of the channel results in
Transcient opening of the channels, thus altering the
ion permeability of the cell.
iii. Also called Ionotropic Receptors

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 Cont.
2. G protein coupled receptors ; the integral
plasma proteins work indirectly via intermediary to
activate or inactivate a separate membrane
associated enzyme channel. The intermediary is a
heterotrimetric Guanosine Triphosphate (GTP)-
binding complex called G protein.
• Also called Metabotropic receptors

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 Cont.
3. Catalytic receptors ; when activated by a ligand,
these integral plasma membrane proteins are
either enzymes or part of an enzymatic complex.

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 Cont.
4. Nuclear receptors :These proteins, located in
the cytosol ,or nucleus, are ligand-activated
transcription factors. These receptors link
extracellular signals to gene transcription.Ligands
includes ;
Steroid hormones:
Mineralocorticoids,Glucocorticoids,Androgens,Estroges,Proge
stins
Others: Thyroid hormones, Retinoic acid, VitaminD,
Prostaglandin

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Hormone EXTRACELLULAR
(testosterone) FLUID The steroid
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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 Signal transduction pathways
• Step 1: Recognition of the signal by its receptor. The
same signaling molecule can sometimes bind to more
than one kind of receptor. For example, ACh can bind to
both ligand-gated channels and G protein–coupled
receptors.
• Step 2: Transduction of the extracellular message into an
intracellular signal or second messenger. Ligand binding
causes a conformational change in the receptor that
triggers the catalytic activities intrinsic to the receptor or
causes the receptor to interact with membrane or
cytoplasmic enzymes. The final consequence is the
generation of a second messenger or the activation of a
catalytic cascade.
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 Cont’d

Step 3: Transmission of the second messenger’s

signal to the appropriate effector. These effectors
represent a diverse array of molecules, such as
enzymes, ion channels, and transcription factors.
Step 4: Modulation of the effector. These events
often result in the activation of protein kinases
(which put phosphate groups on proteins) and
phosphates (which take them off), thereby altering
the activity of other enzymes and proteins

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 Cont’d
Step 5: Response of the cell to the initial stimulus.
This collection of actions represents the summation
and integration of input from multiple signaling
pathways.
Step 6: Termination of the response by feedback
mechanisms at any or all levels of the signaling
pathway.

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Signal transduction pathways

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 RECEPTORS COUPLED TO G PROTEINS
• G protein–coupled receptors (GPCRs) constitute
the largest family of receptors on the cell
surface,with more than 1000 members.
• GPCRs mediate cellular responses to a diverse
array of signaling molecules, such as hormones,
neurotransmitters,vasoactive peptides, odorants,
tastants, and other local mediators.

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 Cont’d
• G protein consist of a single polypeptide chain with seven
membrane-spanning α-helical segments, an extracellular N
terminus that is glycosylated, a large cytoplasmic loop that is
composed mainly of hydrophilic amino acids between
helices 5 and 6, and a hydrophilic domain at the cytoplasmic
C terminus.
• The 5,6-cytoplasmic loop appears to be the major site of
interaction with the intracellular G protein, although the 3,4-
cytoplasmic loop and the cytoplasmic C terminus also
contribute to binding in some cases.
• Binding of the GPCR to its extracellular ligand regulates this
interaction between the receptor and the G proteins, thus
transmitting a signal to downstream effectors. 39
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 GENERAL PROPERTIES OF G PROTEINS

• Heterotrimeric G proteins are

composed of three subunits,α, β,
and γ.
• At least 16 different α subunits

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 G PROTEIN ACTIVATION

• G protein activation follows a cycle.

• In their inactive state, heterotrimeric G
proteins are a complex of α, β, and γ
subunits in which GDP occupies the
guanine nucleotide–binding site of the α
subunit.

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 The activation cycle
• After ligand binding to the GPCR, the activated
receptor interacts with the αβγ heterotrimer to
promote a conformational change that
facilitates the release of bound GDP and
simultaneous binding of GTP.
• This GDP-GTP exchange stimulates dissociation
of the complex from the receptor and causes
disassembly of the trimer into a free α subunit
and βγ complex.
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• The free, active GTP-bound α subunit can now interact
in the plane of the membrane with downstream
effectors such as adenylyl cyclase and phospholipases.
Similarly, the βγ subunit can now activate ion channels
or other effectors.
• The α subunit terminates the signaling events that are
mediated by the α and βγ subunits by hydrolyzing GTP
to GDP and inorganic phosphate (Pi).
• The result is an inactive α-GDP complex that dissociates
from its downstream effector and reassociates with a
βγ subunit thus completing the cycle .
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 Receptors that are ligand gated ion channels

• The receptor is also an ion channel

• Activation by 1st messenger results in a
conformational changes of the receptor that forms
an open channel via cell membrane
• Common in neuron membrane
• Changes in membrane potential constitutes
response to 1st messenger.
• If calcium channel; increased cytosolic calcium

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 CATALYTIC RECEPTORS

• A number of hormones and growth factors bind to

cell surface proteins that have—or are associated
with—enzymatic activity on the cytoplasmic side
of the membrane.
• Have intrinsic enzyme activity

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 CLASSIFICATION OF CATALYTIC RECEPTORS

• Receptor guanylyl cyclases catalyze the generation of

cGMP from GTP.
• Receptor serine/threonine kinases phosphorylate serine
or threonine residues on cellular proteins.
• Receptor tyrosine kinases (RTKs) phosphorylate tyrosine
residues on themselves and other proteins.
• Tyrosine kinase–associated receptors interact with
cytosolic (i.e., non–membrane bound) tyrosine kinases.
• Receptor tyrosine phosphatases cleave phosphate
groups from tyrosine groups of cellular proteins.
1. https://www.youtube.com/watch?v=0mKZRAt0GZg
2. https://www.youtube.com/watch?v=-osiUGKsu7o 50
 Sequence
1. Binding of a specific messenger to the receptor
changes the conformation of the receptor so that
its enzyme portion, located on the cytoplasmic
side is activated
2. Autophosphorylation of the receptor (its own
tyrosine groups)
3. Newly created phosphotyrosines on the
cytoplasmic portion of the receptor then serves as
docking site for cytoplasmic proteins
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 G protein coupled receptors
• It is bound to inactive receptor in the cytosol surface of
the plasma membrane
• Sub unit; alpha, beta and gamma
• Alpha binds to GDP and GTP (GTP is the guanosine analog
of ATP )
• Beta and gamma help alpha to anchor on the cell
membrane
• The alpha subunit is bound to GDP. When a ligand binds
to a G-coupled receptor, this GDP is exchanged for GTP
and the alpha subunit separates from the other subunits.
The separated subunit brings about many biologic effects.
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55
 Cont
• G proteins switch or couple G protein coupled
receptors
• G protein may cause ion channel to open with
resulting electrical signal or in calcium channel
increases in cytosolic calcium ions
• It can activate or inactivate enzymes
• Adenylcyclase and phospholipase C involves G
protein in its actions

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EXAMPLES

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 Adenylcyclase and cAMP
• Activation of the receptor by binding of the 1 st messenger
allows the receptor to activate its associated G protein
• This causes the G protein to activate its effector proteins;
adenylcylase
• Activated adenylcyclase whose catalytic site is in the
cytosol catalyzes the conversion of cytosolic ATP to cyclic
3’5’ AMP (2nd messenger)
• cAMP activates cAMP dependent protein kinase (protein
Kinase A); amplification cascade
• Its action is terminated by cAMP phosphodiesterase
• Caffeine and theophylline inhibits phosphodiesterase 58
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 Protein Kinase A
• The majority of the biological effects of cAMP
are mediated by the activation of protein
kinases.
• Protein kinases regulated by cAMP are classified
as protein kinase A.
• Protein kinase A catalyzes the phosphorylation of
various cellular proteins, ion channels, and transcription
factors.
• This phosphorylation alters the activity or function of the
target proteins and ultimately leads to a desired cellular
response
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 Phospholipase C, diacyglycerol and inositol
triphosphate(IP₃)
• G protein q is activated by a receptor bound to a 1st
messenger which activates a plasma membrane
effector enzyme called phospholipase C
• Phospholipase C leads to breakdown of a plasma
membrane phospholipid called
phosphatidylinositol biphosphate(PIP2) to
diacyglycerol (DAG) and inositol triphosphate (IP₃)
• Both DAG and IP₃ act as 2nd messengers but in
different ways
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 Cont
• DAG activates protein kinase C which
phosphorylates protein; cell response
• Cytosolic IP₃ binds to receptors located on the
ER; ligand gated Ca²⁺ channels that open when
bound to IP₃
• Because {Ca²⁺ } is higher in ER than cytosol,
Ca²⁺ enters into the cytosol=response

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 Control of ion channels by G proteins
• Mechanisms;
1. Ion channel is part of the receptor
2. A G protein directly gates the channel
3. A G protein gates the channel indirectly via a
second messenger

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 Ca²⁺ as second messenger
• Common mechanisms by which stimulation of a cell
leads to an increase in cytosolic Ca²⁺
1. Receptor activation
a. Plasma membrane Ca²⁺ channels open in response to 1 st
messenger; the receptor itself may contain the channel or
may activate a G protein that open the channel via 2 nd
messenger
b. Ca²⁺ is released from ER mediated by IP₃ and Ca²⁺ from ECF
c. Active Ca²⁺ transport out of the cell and inhibited by a 2 nd
messenger
2. Opening of voltage gated Ca²⁺ channels 67
PATHOPHYSIOLOGY OF CHOLERA
• Notice that negative charges now move across the cell from
interstitium to lumen and generate a lumen-negative voltage
that can drive passive Na+ secretion across the tight
junctions (paracellular pathway).
The net process is NaCl secretion, even though the primary
active transporter, the Na-K pump, is pumping Na+ from the
cell to the interstitium.
Secretory cells in the intestine and pulmonary airway
epithelium use this mechanism for secreting NaCl.
• In general, water moves passively across an epithelium in
response to osmotic gradients.
Summary

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