Download lecture-2-hhd - WordPress.com

Human Health and Disease
Lecture 2
Cell Signaling
 Cells can not live in an isolated environment.
 Prokaryotes communicate with each other, other
organisms and surrounding environment.
 Eukaryotes e.g yeasts, slime molds, and
protozoans mate, differentiate and respond to the
environment by secreting pheromones
Cells are able to receive and process signals.
Individual cells receive many signals
simultaneously, and they then integrate the
information they receive into a unified action
plan.
 They also send out messages to other cells both
near and far.


What kind of signals do cells receive?





Most cell signals are chemical in nature.
Prokaryotic organisms have sensors that detect
nutrients and help them navigate toward food
sources.
In multicellular organisms, growth factors,
hormones, neurotransmitters, and extracellular
matrix components are some of the many types
of chemical signals cells use.
These substances can exert their effects locally,
or they might travel over long distances.
Some cells also respond to mechanical stimuli.
For example sensory cells in skin and ear.
Signaling in plants and animals
In plants and animals, extra cellular
signaling molecules control
 Metabolism
 Growth and differentiation of tissues
 Synthesis and secretion of proteins
 Composition of intracellular and
extracellular fluids

General principle signaling
1.
2.
3.
4.
5.
6.
Synthesis of signaling molecules by the
signaling cells
Release of signaling molecules
Transport of the signal to the target cell
Detection of a signal by a specific receptor
protein present on the target cell
A change in cellular metabolism, function
or development triggered by the receptorsignal complex
Removal of the signal, which often
terminate the cellular response
1
3
2
4
5
6
Signaling cell
The series of steps involved signal transduction pathway
7
Cellular responses due to cell
signaling
Changes in the activity or function of
specific enzymes and other proteins
present in the cells
 Changes in the amount of protein
produced by a cell e.g. modification of
transcription factors that stimulate or
repress gene expression

Types of signaling
Types of receptors
Receptors for steroid and
thyroid hormones are
located inside target cells,
in the cytoplasm or
nucleus, and function as
ligand-dependent
transcription factors. That
is to say, the hormonereceptor complex binds to
promoter regions of
responsive genes and
stimulate or sometimes
inhibit transcription from
those genes.
Structure of Intracellular Receptors

Steroid and thyroid hormone receptors are members of a large
group ("superfamily") of transcription factors. In some cases,
multiple forms of a given receptor are expressed in cells, adding to
the complexity of the response. All of these receptors are
composed of a single polypeptide chain that has, in the simplist
analysis, three distinct domains:

The amino-terminus: In most cases, this region is involved in
activating or stimulating transcription by interacting with other
components of the transcriptional machinery. The sequence is
highly variable among different receptors.
DNA binding domain: Amino acids in this region are responsible
for binding of the receptor to specific sequences of DNA.
The carboxy-terminus or ligand-binding domain: This is the
region that binds hormone.


NLS in Intracellular Receptors

In addition to three core domains, two
other important regions of the receptor
protein are a nuclear localization
sequence, which targets the protein to
nucleus, and a dimerization domain, which
is responsible for latching two receptors
together in a form capable of binding
DNA.
Hormone-Receptor Binding and Interactions
with DNA

Being lipids, steroid hormones enter the cell by simple diffusion
across the plasma membrane. Thyroid hormones enter the cell by
facilitated diffusion. The receptors exist either in the cytoplasm or
nucleus, which is where they meet the hormone. When hormone binds
to receptor, a characteristic series of events occurs:

Receptor activation is the term used to describe conformational
changes in the receptor induced by binding hormone. The major
consequence of activation is that the receptor becomes competent to
bind DNA.
Activated receptors bind to "hormone response elements", which are
short specific sequences of DNA which are located in promoters of
hormone-responsive genes. In most cases, hormone-receptor
complexes bind DNA in pairs.
Transcription from those genes to which the receptor is bound is
affected. Most commonly, receptor binding stimulates transcription. The
hormone-receptor complex thus functions as a transcription factor.


Classification of hormones
Lipophillic Hormones with intracellular
receptors e.g steroid, thyroxine, retinoic
acid
 Hydrophillic with cell-surface receptors
e.g peptide hormones (insulin growth
factor and glucagon), small charge
molecules (epinephrine and histamine)
 Lipophillic with cell surface receptor e.g.
prostaglandins

Cell Surface Receptors
Receptor protein exhibit ligand
binding effect
Receptor present on Plasma or nuclear
membrane has ligand binding sites
 Signaling molecules (hormones,
pheromones or neurotransmitters) act as
ligands
 Confirmational change occurs in the
receptor that initiate a sequence of
chemical reactions
 Receptor proteins are specific for each
horomone







Different cells have different sets of receptor for
the same ligand and each of which induces a
different response
Different cells respond in a variety of way to the
same ligand (e.g. acetylcholine)
Different ligands can induce the same cellular
response in some cells (glucagon/epinephrine)
In most receptor-ligand system, the ligand do not
have any function except to bind to receptor
Upon binding it changes the properties of
receptor which then produce signals to the cell
that a specific product is present
Target cells often degrade or modify the ligand to
terminate or modify their response
The same signaling molecule can
induce different responses in different
target cells
Gap Junctions Allow Signaling Information
to Be Shared by Neighboring Cells
Signals are passed to the neighboring cells through
gap junctions.
 These are specialized cell-cell junctions that can
form between closely apposed plasma membranes,
directly connecting the cytoplasms of the joined
cells via narrow water-filled channels.

(a)
(b)
(c)
(d)
(c1)
(c2)
(c3)
(c4)
(c5)
Each Cell Is Programmed to Respond to Specific
Combinations of Signaling Molecules



Each cell is exposed to many different signals known as
combinatorial signaling.
Each cell type displays a set of receptors that enables it to
respond to a corresponding set of signaling molecules.
These signaling molecules work in combinations to regulate the
behavior of the cell. Many cells require multiple signals ( green
arrows) to survive and additional signals ( red arrows) to
proliferate; if deprived of all signals, these cells undergo
programmed cell death.
Erythropoietin and formation of RBCs
In the absence of EPO, CFU-E undergoes apoptosis
Optimal red blood cell (RBC) production requires both erythropoietin (as the controlling
factor) and iron (as the raw material). Several factors can impair RBC production; inhibit iron
availability, and/or shorten RBC life span . BFU-E, burst-forming unit erythroid; CFU-E, colonyforming unit erythroid.
Uremic toxins: products of metabolism that accumulate in the body with renal failure e.g. urea,
creatinine
PTH: parathyroid hormone
JAK/STAT pathway
Mutation in
EPOR leads to
embryonic cell
death due to
severe anemia,
study was
conducted on
mice
Janus kinase (JAK)
Signal Transducer and Activator of Transcription (STAT)
Involvement of G- Protein in Cell
Signaling
General elements of GPCRs
Most abundant class of receptors
 Found in organisms from yeast to man
1. A receptor with 7 membrane-spanning
domains
2. A coupled trimeric G protein
3. A membrane bound effector protein
4. Feedback regulation and desensitization of
the signalling pathway
5. A 2nd messenger present in many GPCRs.

Second messengers are molecules that
relay signals from receptors on the cell
surface to target molecules inside the cell, in
the cytoplasm or nucleus.
 These components of GPCRs can be mixed
and matched to achieve an astonishing
number of different pathways
 GPCR pathways usually have short term
effects in the cells
 Allow the cells to respond rapidly to a
variety of signals like environmental stimuli
(light) or hormonal stimuli (epinephrine)

General features
 GPCRs have same orientation in the
membrane , 7 transmembrane alphahelical regions, 4 extra cellular segments,
4 cytosolic segments

G Protein
•Guanine nucleotide-binding
proteins, family of proteins involved in
transmitting chemical signals originating
from outside a cell into the inside of the
cell.
•G proteins function as molecular
switches. Their activity is regulated by
their ability to bind to and
hydrolyze guanosine triphosphate (GTP)
to guanosine diphosphate (GDP).
•When they bind GTP, they are 'on', and,
when they bind GDP, they are 'off'.
•G proteins belong to the larger group
of enzymes called GTPases.
Gβ§
Various ligands use G-protein-coupled receptors (GPCRs) to stimulate membrane,
cytoplasmic and nuclear targets. GPCRs interact with heterotrimeric G proteins
composed of , and subunits that are GDP bound in the resting state. Agonist binding
triggers a conformational change in the receptor, which catalyses the dissociation of
GDP from the subunit followed by GTP-binding to G and the dissociation of G from
G subunits1. The subunits of G proteins are divided into four subfamilies: Gs, Gi, Gq and
G12, and a single GPCR can couple to either one or more families of G proteins. Each G
protein activates several downstream effectors.
Opening of ion channels
GPCRs that activate adenylyl clase
Lecture prepared from
The Cell: A Molecular Approach. 2nd
edition
http://www.ncbi.nlm.nih.gov/books/NBK989
8/
 Molecular Cell Biology, Lodish and co
5Edition, Chapter 15
