Receptors and Cell Signaling-Dr B K Manjunatha Goud

Receptors and cell signaling
DR B K Manjunatha Goud
MBBS MD
Faculty of Biochemistry
Date: 26/09/2019
Time: 08.30am-10.30am
At the end of the session student shall be able to
Define and classify cytoplasmic and nuclear

receptors.
Describe the structure of G-proteins and its
mechanism of action through 2nd messenger’s
cAMP, Phosphatidyl inositol triphosphate &
diacyl glycerol in cell signaling.
40 year male admitted to the emergency ward with
history of passing of loose stools for last 12 hours. He
had history of having his dinner last night in a sea
food restaurant. On examination he has severe
dehydration and his stool examination revealed
cholera.
What is cholera?
Why the person had severe diarrhea after
consumption of sea food?
What is the Biochemical basis for diarrhea in cholera?
Which receptors are involved in the action of cholera
toxin?
Receptor – a specific
protein that specifically
binds a signaling molecule
to initiate a response in a
target cell
Cell responses :
◦ changes in gene expression
◦ cell morphology
◦ cell movements
Plasma membrane
receptors
◦ Ligand – hydrophilic
signaling molecules
Intracellular Receptor
◦ Ligand – hydrophobic
signaling molecules
Plasma membrane receptor (lipid insoluble)
1. Receptors function as ion channel.

2. Receptor function as enzyme.
3. Receptors that bound to and activate
cytoplasmic JAK(Janus Kinase).
4. Receptors activate G protein.
Protein receptor constitute
of ion channel
Activation of the receptor

by the first messenger
The opening results

increase diffusion of ions to
the channel
E.g- Acetyl choline receptor
• Receptors that posses intrinsic
enzyme activity are all protein
kinases
• Binding of specific messenger to
the receptor changes its
conformation.
• Enzymatic portion in cytoplasm is
activated
• The receptor phosphorylates its
own tyrosine group
• The phosphotyrosine bind other
protein which leads signaling
pathways within the cell.
E.g – Insulin receptor
G Protein is a protein bound to the receptor
located on the inner cytosolic surface of the
plasma membrane
• Activation of the receptor by
binding of the first
messenger
• G protein activated
• G protein stimulate effector
protein adenylate cyclase
• Conversion to cAMP
• cAMP act as second
messenger
• Cell response to the first
messenger
The enzymatic activity reside not in the receptor but
in the separate cytoplasmic kinases.
The binding of the first messenger to the receptor

causes conformational changes that leads to
activation of the JAK kinase.
The results of these pathways is the synthesis of

new proteins which mediate the cells response to
the messenger
Eg. Growth hormones, growth factor actions are
mediated by this mechanism.
Intracellular receptors – located either in cytosol
or in the nucleus of the cell. They bind to the
lipophilic ligands like steroid hormones.
◦ Cytoplasmic – located in the cytoplasm of the cell. E.g.

– receptors for hormone cortisol.
◦ Nuclear – Located in the nucleus of the cell. e.g –
receptors for estradiol, testosterone
First messengers: Messengers bind to specific
receptor.
Second messengers: non-protein substances
enter the cytoplasm and diffuse throughout the
cell and transmit signals
Protein kinase: any enzymes that
phosphorylates other proteins by transferring
phosphate group
The process of converting
extracellular signals into
cellular responses.
Extracellular signaling
molecules (ligands) -
substances synthesized
and released by signaling
cells and produce a specific
response only in target cells
that have receptors for the
signaling molecules.
Endocrine Signaling - signaling molecules
(hormones) act on target cells distant from their
site of synthesis by cells of endocrine organs.
Paracrine Signaling - the signaling molecules
(neurotransmitters) released by a cell only affect
target cells in close proximity to it.
Autocrine Signaling - cells respond to
substances (growth factors) which they
themselves release.
Communication by extracellular signals
usually involves six steps:
1. Synthesis and
2. Release of the signaling molecule by the signaling
cell
3. Transport of the signal to the target cell
4. Detection of the signal by a specific receptor protein
5. A change in cellular metabolism, function, or
development triggered by the receptor-signal
complex ;and
6. Removal of the signal, which often terminates the
cellular response.
Two types
Pathway via cell surface

receptors.
◦ E.g – Action of hormones –
glucagon, Thyroid stimulating
hormone
Pathway via intracellular

receptors.
◦ E.g – Thyroid hormones,
steroid hormones
They mainly exert their action through
SECOND MESSENGERS
Second messengers – e.g
3’,5’ cyclic AMP (cAMP)

3’,5’ cyclic GMP (cGMP)
1,2 diacylglycerol (DAG)
Inositol 1,4,5 triphosphate (IP3)
Calcium
GPCR has seven trans
membrane domains
GTP is a trimeric protein( α
βγ)
Coupled directly to
activated receptors
GTP ases – convert GTP
to GDP + Pi
Active- when GTP is
bound
Inactive – when GDP is
bound
G proteins
There are many G proteins,
each being used for different
signal transduction pathway. + Ligand
G proteins which stimulate
adenylate cyclase is – G
stimulatory( Gs) and inhibit is
G inhibitory(Gi)
The α subunit of Gs and Gi
are different but β and γ are
the same.
GPCR activate events altering
concentrations of intracellular
mediators
(Second Messengers)
Common second
messengers:
◦ Cyclic AMP (cAMP)
◦ Calcium (Ca++)
Second messenger
produced from hydrolysis of
pyrophosphate from ATP
Synthesized by Adenylyl
Cyclase
Degraded by cAMP
phosphodiesterase to form
5’AMP.
cAMP activates proteins
kinases and bring about
cellular response.
hormone
Inhibitor
RS Ri
AC
GTDPP

 GDP
GTP 4 ATP
AT P
Inactive
Protein protein
4 cAMP kinase
Adenylate cyclase ADP

Active
Signaling System protein
Cell response
cAMP activates glycogen phosphorylase
(glycogenolysis)
cAMP inhibits glycogen synthase (Glycogenesis)
Insulin inhibits cAMP
Glucagon and Epinephrine activates cAMP
Three types:
1. Tyrosine kinase receptors
2. JAK-STAT receptors (janus kinase/ signal

transducer and activator of transcription).
3. Serine/threonine kinase receptors.

Insulin action
Insulin receptor exists as a
preformed dimer.
Each half containing alpha
and beta subunits.
Autophosphorylate each other
when insulin binds and
thereby activates the receptor.
Activated phosphorylated
receptor binds to the IRS
(insulin receptor substrate)
IRS is Phosphorylated at
multiple sites creating multiple
binding sites for proteins and
initiate the response.
The intracellular Ca2+ concentration is less than
extracellular concentration. Hormones can
increase cytosolic Ca2+
◦ By altering the permeability of the membrane
◦ The action of Ca-H+ ATP ase pump
◦ By releasing the intracellular Ca2+ stores.
◦ Calmodulin – Ca2+ dependent regulatory protein
Has got four calcium binding sites
Ca2+ - Calmodulin complex will activate many enzymes in
metabolic pathway
Eg- Phosphorylase kinase(in muscle), glycogen synthase,
The intracellular messengers generated from PIP2, a
membrane phospholipids are Inositol 1,4,5
triphosphate(IP3) and diacylglycerol(DAG)
PIP2 phospholipase IP3 + 1,2 DAG
Stimulate the endoplasmic reticulum to release Ca2+.

The increased intracellular Ca2+ then triggers process like smooth
muscle contraction, glycogen break down etc
IP3 action is short lived and rapidly degraded into

Inositol 1,4 biphosphate.
PIP2 phospholipase IP3 + 1,2 DAG
◦ This being non polar is retained in the membrane, where it

serves as second messenger.
◦ DAG activates membrane bound protein kinase C for which
Ca2+ is required.(obtained from IP3).
◦ Protein kinase C phosphorylate the target proteins
 Hormone - Atrial
Natriuretic peptide(ANP)
– in heart it causes less
forceful contractions
 cGMP is formed from
GTP by the enzyme
Guanylate cyclase which
is membrane bound.
 Nitric oxide stimulate the
formation of cGMP and
causes vasodilation
 cGMP is also involved in

the rhodopsin cycle
(vision, visual cycle)
Case discussion
CFTR-gated channel(cystic fibrosis trans
Cholera A toxin liberated by vibrio
cholera membrane conductance regulator)
binds and activates
G αs subunit of heterotrimeric G-
proteins and “turn it on”.
Increased levels of cAMP
High levels of protein kinase A(PKA)
PKA phosphorylates and activates the

CFTR channel,
Excessive secretion of chloride ion and Other examples for cAMP mediated
Na+ ion into the intestinal lumen. action
Glucagon and Glucocorticoids: stimulate
gluconeogenesis
Associated loss of water, resulting in Epinephrine and glucagon: stimulate
vomiting and watery diarrhea. Glycogenolysis
Reference Book:
Text book of Biochemistry By DM

Vasudevan 8th edition
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Receptors and cell signaling

Define and classify cytoplasmic and nuclear

1. Receptors function as ion channel.

Activation of the receptor

The opening results

The binding of the first messenger to the receptor

The results of these pathways is the synthesis of

◦ Cytoplasmic – located in the cytoplasm of the cell. E.g.

Pathway via cell surface

Pathway via intracellular

Second messengers – e.g

3’,5’ cyclic AMP (cAMP)

Adenylate cyclase ADP

1. Tyrosine kinase receptors

2. JAK-STAT receptors (janus kinase/ signal

3. Serine/threonine kinase receptors.

PIP2 phospholipase IP3 + 1,2 DAG

Stimulate the endoplasmic reticulum to release Ca2+.

IP3 action is short lived and rapidly degraded into

◦ This being non polar is retained in the membrane, where it

 cGMP is also involved in

Increased levels of cAMP

High levels of protein kinase A(PKA)

PKA phosphorylates and activates the

Text book of Biochemistry By DM

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