HORMONES

AND RECEPTORS

Sri Wahyuni
Department of Biochemistry
Faculty of Medicine
Universitas Malikussaleh
Lhokseumawe
CELL COMMUNICATION
In human, different cell types carry out different
functions

This specialized function requires cells to

communicate with each other.
The cells communicate through secretion of chemical
messengers that carry a signal to another cell.

Signals change actions of intracellular proteins

(metabolic enzymes, gene regulatory proteins, ion
channels, or cytoskeletal proteins) in target cells
Chemical Messengers
Chemical Messengers:
In nervous system, they are called neurotransmitters
In endocrine system, they are hormones,
In immune system, they are called cytokines.

• Additional chemical messengers include

retinoids, eicosanoids, and growth factors.
Chemical Messengers
• Classification of chemical messengers depending on
distance between secreting and target cells:
 endocrine (travel in blood)
 paracrine (travel between nearby cells)
 autocrine (act on same cell or on nearby cells of same
type).

1. Endocrine hormone:
• is secreted by a specific cell type (endocrine gland)
• enters blood,
• It’s target cells is distance away.
Endocrine, Paracrine, and Autocrine
2. Paracrine actions on nearby cells, and cells plays
a role in specificity of response.
• E.g. acetylcholine and other neurotransmitters (for
synaptic transmission).

• Acetylcholine activates acetylcholine receptors located

across synaptic cleft from signaling nerve and not all
muscles with acetylcholine receptors.

• Paracrine actions are also limiting immune response to

a specific location in body (helps prevent the
development of autoimmune disease).
Endocrine, Paracrine, and Autocrine

3. Autocrine actions involve a messenger acting on cell from

which it is secreted, or on nearby cells (same type as
secreting cells).
Chemical Messengers
Chemical messengers
(signaling molecules) transmit
messages between cells.
secreted from cell in response to
a specific stimulus
 travel to a target cell and bind
to a specific receptor and elicit a
response (Fig. 1).

Fig. 1. General features of chemical messengers.

Receptors and Signal Transduction
Receptors contain
a binding site specific for a single chemical messenger
another binding site involved in transmitting message.

Binding site may interact with another protein or with DNA:

either plasma membrane receptors or intracellular binding
proteins (Fig.1).

When a chemical messenger binds to a receptor:

Signal is converted into an intracellular response.
This conversion is called signal transduction.
Receptors and Signal Transduction
Most plasma membrane receptors fall into
categories of
• ion channel receptors
• tyrosine kinase receptors
• tyrosine-kinase associated receptors (JAK-STAT
receptors)
• serine-threonine kinase receptors
• heptahelical receptors
Receptors and Signal Transduction
1. Ion Channel Reseptors
Ion channel receptors are similar in structure to nicotinic
acetylcholine receptor
Ligand-receptor complex change conformational receptor
produce signal transduction
Neurotransmitters and some neuropeptides use ion channel
receptors.
 Acetylcholine (Ach)
Acetylcholine diffuses across
synaptic cleft and bind plasma
membrane receptors on muscle
cells (nicotinic acetylcholine
receptors).

As acetylcholine binds to receptor,

a conformational change opens
narrow portion of channel,
so Na can diffuse in and K diffuse out

The change in ion concentration triggers cellular response—

contraction of fiber.
 The Na & K movements cause
membrane polarization that is
transmitted throughout muscle fiber by
T-tubule system.

 Membrane polarization activate

receptor in T-tubules so ryanodine
receptor in sarcoplasmic reticulum is
activated (depolarization-induced
calcium release from SR into
sarcoplasm).

 In cardiac muscle, calcium release from

T-tubules, and this small calcium release
is responsible for activation of cardiac
ryanodine receptor (calcium-induced
calcium release) to release large
amounts of calcium into sarcoplasm.
Releasing of calcium from sarcoplasmic reticulum of skeletal muscle
2. Tyrosine Kinase Receptors
• Several types of receptors are kinases or bind kinases
• Intracellular domain of receptor is a kinase
that is activated when messenger binds to
extracellular domain.

Receptor kinase phosphorylates an amino acid residue on receptor

(autophosphorylation) or an associated protein.
Message is propagated through signal transducer proteins that
bind to activated messenger–receptor complex
3. tyrosine-kinase associated receptors (JAK-STAT receptors), serine-
threonine kinase receptors

Intracellular domain of this receptor is a kinase that is activated

when messenger binds to extracellular domain.
Receptor kinase phosphorylates an amino acid residue on receptor
(autophosphorylation) or an associated protein.
Message is propagated through signal transducer proteins that
bind to activated messenger–receptor complex (e.g.,STAT, or
Smad).

Jak-Stat receptors Serine/threonine kinase receptors

3. HEPTAHELICAL RECEPTORS

Heptahelical receptors are most common

type of plasma membrane receptor.
They work through second messengers
(nonprotein: cAMP), generated inside cell
in response to messenger binding to
receptor

Hormone/cytokine /neurotransmitter
(“first” messenger) transmit message to
intracellular

Because second messengers in low, message

can be rapidly initiated and terminated.
Types of Chemical Messengers
• Three major signaling systems in body use chemical
messengers: nervous system; endocrine system; immune system.

1. Nervous system secretes two types of messengers:

 Neurotransmitters (biogenic amines): are nitrogen-
containing molecules (AA or derivatives of AA).

 Neuropeptides : usually small peptides (4 - 35 AA),

secreted by neurons, as neurotransmitters at synaptic
junctions or secreted into blood as neurohormones.
2. ENDOCRINE SYSTEM
Endocrine hormones are secreted from specific endocrine
cells in endocrine glands and transport through blood to
reach target cells.
• E.g. Insulin, secreted from pancreas cells
• Many of these endocrine hormones also exert paracrine or
autocrine actions.

• Some compounds normally considered hormones are more

difficult to categorize.
retinoids are derivatives of vitamin A
vitamin D are usually classified as hormones, although they
are not synthesized in endocrine cells.
3. IMMUNE SYSTEM
Messengers of immune system (cytokines) are small
proteins with a molecular weight of + 20,000 daltons.

Cytokines regulate a network of responses to kill

microorganisms.

Different classes of cytokines (interleukins, tumor

necrosis factors, interferons, and colony-stimulating
factors) are
secreted by cells of immune system
usually alter behavior of other cells in immune system by activating
transcription of genes for proteins involved in immune response.
4. EICOSANOIDS

Including prostaglandins, thromboxanes, & leukotrienes (derived

from arachidonic acid, a 20-C PUFA)
control cellular function in response to injury
usually present in as part of membrane lipid phosphatidylcholine.

Most cell in body produces an eicosanoid in response to tissue

injury, but different cells produce different eicosanoids.

The eicosanoids act principally in paracrine and autocrine

functions.
5. GROWTH FACTORS

Growth factors stimulate of cellular proliferation.

i.e., platelets aggregating at injured site of blood vessel
secrete PDGF (platelet-derived growth factor).
PDGF stimulates proliferation of nearby smooth muscle
cells, which form a plaque covering injured site.

Some growth factors are considered hormones, and some

have been called cytokines

Each chemical messengers has specific receptor, which will

bind no other messenger.
Intracellular Transcription Factor Receptors
 The messengers must be hydrophobic molecules able to diffuse
through plasma membrane into cells.
 Most of intracellular receptors for lipophilic messengers are gene-
specific transcription factors.
 A transcription factor is a protein that binds to a specific site on
DNA and regulates rate of transcription of a gene (i.e., synthesis of
mRNA).

 External signaling molecules bind to

transcription factors bind to a
specific sequence on DNA and regulate
expression of only certain genes
Gene-specific or site-specific
transcription factors.
Steroid Hormone/Thyroid Hormone Superfamily of
Receptors
Lipophilic hormones use intracellular gene-specific
transcription factors:
steroid hormones, thyroid hormone, retinoic & vitamin
D.

water-insoluble, transported in blood bound to

serum albumin, steroid hormone binding globulin (SHBG) and
thyroid hormone-binding globulin (TBG).

Their intracellular receptors are steroid hormone/thyroid

hormone superfamily of receptors.
Most steroid hormone/thyroid hormone superfamily of
receptors in nucleus, but some are in cytoplasm
glucocorticoid receptor is associated with heat shock proteins.

When glucocorticoid binds, the receptor undergoes a

conformational change and dissociates from heat shock
proteins, exposing a nuclear translocation signal.

The complex receptor-hormone translocates to nucleus and

portion of DNA, called hormone response element
e.g., glucocorticoid receptor binds to glucocorticoid response element,
GRE

Binding of hormone changes its activity and its ability to

associate with, or disassociate from, DNA.
Plasma membrane receptors
are proteins with
an extracellular domain binds chemical messenger
one or more membrane spanning domains (helices)
an intracellular domain initiates signal transduction.

Their messengers are polar molecules: peptide

hormones, cytokines, and catecholamines:
 cannot rapidly cross plasma membrane
 mmust bind to a plasma membrane receptor.
Plasma Membrane Receptors and Signal Transduction
Ligand binds extracellular domain of its receptor
causes
a conformational change that is communicated to
intracellular domain through rigid -helix of
transmembrane domain.

activated intracellular domain initiates a signal

transduction pathway that involves binding of a specific
intracellular signal transduction protein.
Two effect types on cell of signal transduction for
plasma membrane receptors

1. Rapid and immediate effects on cellular ion

levels or activation/inhibition of enzymes and/or

1. slower changes in gene expression rate for a

specific proteins.

 Often, a signal transduction pathway will

diverge to produce both kinds of effects.
Signal Transduction
Hormonal regulation depends on
transduction of hormonal signal across plasma
membrane to specific intracellular sites, particularly
nucleus.

Signal transduction:
receptor⎯→ transducers⎯→effectors.

Receptor perceives signal, transducers relay signal,

and effectors convert signal into an intracellular
response.
Characteristics of signal transduction systems
 Transmembrane communication of hormonal signals by receptor
proteins

 Protein interaction domains that selectively recognize specific

structural motifs and bind them with high affinity and specificity

 Clustering of membrane receptors and their ligands in large

aggregates called signalsomes

 Reversible covalent modifications that change function of

certain proteins and lipids (including phosphorylation, methylation,
acetylation, ubiquitylation, hydroxylation, and cleavage)
Characteristics of signal transduction systems
 Second messengers that bind to specific targets, changing their
activity and behavior

 Intracellular signaling pathways, often involving a series of

enzymes (such as protein kinases), that link receptors to their
downstream functional targets

 Cooperativity
 Spatial and temporal control of signals and messengers
 Integration of signals
 Converging and diverging networks
 Signal amplification
 Desensitization and adaptation
FIGURE A complete signal transduction
pathway that connects a hormone
receptor with transcription events in
nucleus. A number of similar pathways
have been characterized.
 Signal Transduction
Signal Transduction for Intracellular Receptors
Most intracellular receptors are gene-specific
transcription factors (proteins bind DNA & regulate
transcription of certain genes

Signal Transduction for Plasma Membrane Receptors.

Mechanisms of signal transduction include:
• phosphorylation of receptors at tyrosine residues
(receptor tyrosine kinase activity)
• conformational changes in signal transducer proteins
• increases in levels of intracellular second messengers.
Second messengers are non protein generated inside cell in
response to hormone binding that continue transmission of
message:
3,5-cyclic AMP (cAMP)
inositol trisphosphate (IP3)
diacylglycerol (DAG).

Signaling often requires a rapid response and termination of

message by
degradation of messenger or second messenger,
automatic G protein clock
deactivation of signal transduction kinases by phosphatases,
Others.
Signal Transduction through Tyrosine Kinase Receptors
One molecule of growth factor generally binds two molecules of
receptor and promotes their dimerization (Fig.)
When receptor dimer has formed, intracellular tyrosine kinase
domains of receptor phosphorylate each other on certain tyrosine
residues (autophosphorylation). Phosphotyrosine residues form
specific binding sites for signal transducer proteins.
Phosphatidylinositol Phosphates in Signal Transduction

Phosphatidylinositol phosphates serve 2

different functions in signal transduction:
1. Phosphatidylinositol 4,5 bisphosphate (PI-4,5-bisP)
can be cleaved to generate 2 intracellular second
messengers: diacylglycerol (DAG) and inositol
trisphosphate (IP3);

1. Phosphatidylinositol 3,4,5 trisphosphate (PI-3,4,5-trisP)

can serve as a plasma membrane docking site for signal
transduction proteins.
PI in inner leaflet of plasma membrane is converted to PI-4,5-
bisP by kinases that phosphorylate inositol.
PI-4,5-bisP is cleaved by
1. phospholipase C-isozyme to generate IP3 and DAG.
Phospholipase isozyme C (PLC) is activated by tyrosine kinase
growth factor receptors
Phospholipase C is activated by a heptahelical receptor–G protein
signal transduction pathway.

2. phosphatidylinositol 3 kinase (PI 3-kinase) to form PI

-3,4,5- trisP.
PI-3,4,5- tris P (and PI -3,4 bis P) form membrane docking
sites for proteins containing a certain sequence of amino
acids called pleckstrin homology (PH) domain.
PI 3- kinase is activated by binding to a specific
phosphotyrosine site on a tyrosine kinase receptor or
receptor-associated protein.
Major route for generation of
inositol 1,4,5-trisphosphate (IP3)
phosphatidylinositol 3,4,5
trisphosphate (PI-3,4,5-trisP).

PI 3-kinase phosphorylates PI-4,5-

bisP and PI-4P at 3 position.
 Insulin Reseptor
 in membrane as a dimer, with each half containing subunit.
 Subunits autophosphorylate each other when insulin binds, thereby
activating the receptor.

 Activated phosphorylated receptor binds insulin receptor substrate

(IRS).
 Activated receptor kinase phosphorylates IRS at multiple sites,
creating multiple binding sites for different proteins with SH2
domains.

 One of sites binds Grb2, leading to activation of Ras and MAP kinase
pathway.
 Grb2 is anchored to PI-3,4,5-trisP in the plasma membrane through its
PH (pleckstrin homology) domain.
 At another phosphotyrosine site, PI 3-kinase binds and is activated.

 At a third site, phospholipase C(PLC) binds and is activated.

 Insulin receptor can also transmit signals through a direct docking
with other signal transduction intermediates.
 The insulin receptor is a dimer of two membrane-spanning– pairs.
 Tyrosine kinase domains are shown in blue, and arrows indicate auto-
crossphosphorylation.
 Activated receptor binds IRS molecules (insulin receptor substrates)
and phosphorylates IRS at multiple sites, thereby forming binding
sites for proteins with SH2 domains: Grb2, phospholipase C(PLC), and
PI 3-kinase.

 These proteins are associated with various

phosphatidylinositol phosphates
(all designated with PIP) in the plasma
membrane.
Signal pathway initiated by insulin receptor complex involving
PI 3-kinase leads to activation of protein kinase B, a serine-
threonine kinase that mediates many of the downstream effects
of insulin .

PI 3- kinase binds and phosphorylates PI-4,5- bis P in the

membrane to form PI-3,4,5- trisP.

Protein kinase B and PDK1 (phosphoinositide-dependent

kinase-1) are recruited to the membrane by their PH domains,
where PDK1 phosphorylates and activates protein kinase B.

Many other signal transducer proteins have PH domains and

are docked at the membrane, where they can find and bind
each other.
 Insulin receptor–protein kinase B signaling pathway.
 Ins: insulin
 IRS: insulin receptor substrate
 PH domains: pleckstrin homology domains
 PDK1: phosphoinositide-dependent protein kinase 1
 PKB: protein kinase B

 The final phosphorylation step that activates PKB is shown in blue.

SIGNAL TERMINATION
Some signals that modify metabolic responses of cells or
transmit neural impulses, need to turn off rapidly when
hormone is no longer being produced.

Other signals that stimulate proliferation, turn off more

slowly.

Signals regulating differentiation may persist throughout

our lifetime.

Many chronic diseases are caused by failure to terminate a

response at appropriate time.
SIGNAL TERMINATION
First level of termination is chemical messenger
itself .

When stimulus is no longer applied to secreting

cell, messenger is no longer secreted, and existing
messenger is catabolized.
E.g. many polypeptide hormones (insulin) are taken up
into liver and degraded.
Termination of acetylcholine signal by
acetylcholinesterase
SIGNAL TERMINATION
Within each pathway of signal transduction, signal may be
turned off at specific steps:
receptor might be desensitized to messenger by
phosphorylation.
G proteins automatically terminate messages as they
hydrolyze GTP.
degradation of second messenger (e.g.,
phosphodiesterase cleavage of cAMP).
removing phosphate groups from proteins by
phosphatases.
Each of these terminating processes is also highly regulated.
Sites of signal termination.
Processes that terminate
signals are shown in blue.