Cell signalling,cell transduction,cell-cell interactions mechanisms,Science,Cell biology topic for cell transduction or signalling

1. CELL SIGNALING
By: ASHISH KELWA

2. Cellular Signaling
Many living organisms contain billions of cells that carry out diverse
functions. In order for the cells to cooperate, cells need to be able to
communicate with each other. Many of the genes that cells are capable
of synthesizing are thought to be involved in cellular signaling.
Signal transduction comes from the verb to 'transduce' meaning to
'lead across'. In biology signal transduction is the process by which an
extracellular signaling molecule activates a membrane receptor that in
turn alters intracellular molecules to create a response. The chemical
signal binds to the outer portion of the receptor, changing its shape and
conveying another signal inside the cell.

3. Environmental stimuli
With single-celled organisms, the variety of signal
transduction processes influence its reaction to its
environment.
With multicellular organisms, numerous processes are
required for coordinating individual cells to support the
organism as a whole; the complexity of these processes
tend to increase with the complexity of the organism.
Sensing of environments at the cellular level relies on
signal transduction; many disease processes, such
as diabetes and heart disease arise from defects in
these pathways, highlighting the importance of this
process in biology and medicine.

4. Various environmental stimuli exist that initiate signal transmission
processes in multicellular organisms; examples include photons hitting
cells in the retina of the eye, and odorants binding to odorant
receptors in the nasal epithelium. Certain microbial molecules, such as
viral nucleotides and protein antigens, can elicit an immune
system response against invading pathogens mediated by signal
transduction processes.

5. Types of cellular signaling
Extra cellular signaling or chemical signaling.
Cell's direct signaling or intracellular signaling.

6. Extracellular signaling
Signaling by extracellular, secreted molecules can be classified into
three types — endocrine, paracrine, or autocrine — based on the
distance over which the signal acts.

7. Endocrine signaling
In endocrine signaling, signaling molecules, called hormones, act on
target cells distant from their site of synthesis by cells of endocrine
organs. In animals, an endocrine hormone usually is carried by the
blood from its site of release to its target.

8. Paracrine signaling
In paracrine signaling, the signaling molecules released by a cell only
affect target cells in close proximity to it. The conduction of an electric
impulse from one nerve cell to another or from a nerve cell to a muscle
cell (inducing or inhibiting muscle contraction) occurs via paracrine
signaling.

10. Autocrine signaling
Cells respond to substances that they themselves release. Many growth
factors act in this fashion, and cultured cells often secrete growth
factors that stimulate their own growth and proliferation. This type of
signaling is particularly common in tumor cells, many of which
overproduce and release growth factors that stimulate inappropriate,
unregulated proliferation of themselves as well as adjacent non tumor
cells; this process may lead to formation of tumor mass.

11. Cell direct contact signaling
Three types:
 Gap junctions
Surface protein interactions
Receptors

12. Receptors
A receptor is a molecule found on the surface of a cell,
which receives specific chemical signals from
neighboring cells or the wider environment within an
organism. These signals tell a cell to do something—for
example to divide or die, or to allow certain molecules
to enter or exit the cell.
Receptors are protein molecules, embedded in either
the plasma membrane (cell surface receptors) or
the cytoplasm (nuclear receptors) of a cell, to which
one or more specific kinds of signaling molecules may
attach.

13. Types of Receptors
There are a number of receptor classes that are used in different signaling pathwa
The two more predominant are:

14. The conformational change in the receptor upon ligand binding
activates a G protein, which in turns activates an effector protein that
generates a second messenger.
These receptors have a catalytic
activity that is activated by
binding of the ligand. An example
are tyrosine-kinase receptors.
Binding of an often dimeric ligand
induces dimerization of the
receptors that leads to cross
phosphorylation of the cytosolic
domains and phosphorylation of
other proteins.

15. A molecule which binds (attaches) to a receptor is called a ligand, and
may be a peptide (short protein) or other small molecule, such as a
neurotransmitter, a hormone, a pharmaceutical drug, or a toxin. Each
kind of receptor can bind only certain ligand shapes. Each cell typically
has many receptors, of many different kinds. Simply put, a receptor
functions as a keyhole that opens a biochemical pathway when the
proper ligand is inserted.

16. Structure
The shapes and actions of receptors are studied by X-ray
crystallography, dual polarization interferometry, computer modelling,
and structure-function studies, which have advanced the understanding
of drug action at the binding sites of receptors. Structure activity
relationships correlate induced conformational changes with bio
molecular activity, and are studied using dynamic techniques such
as circular dichroic and dual polarization interferometry.

17. Binding and activation
Ligand binding is an equilibrium process. Ligands bind to receptors and
dissociate from them according to the law of mass action.
One measure of how well a molecule fits a receptor is the binding
affinity, which is inversely related to the dissociation constant Kd. A good
fit corresponds with high affinity and low Kd. The final biological
response (e.g. second messenger cascade, muscle contraction), is only
achieved after a significant number of receptors are activated.
The receptor-ligand affinity is greater than enzyme-substrate
affinity. Whilst both interactions are specific and reversible, there is no
chemical modification of the ligand as seen with the substrate upon
binding to its enzyme.

18. Constitutive activity
A receptor which is capable of producing its
biological response in the absence of a bound
ligand is said to display "constitutive activity". The
constitutive activity of receptors may be blocked
by inverse agonist binding. Mutations in receptors
that result in increased constitutive activity
underlie some inherited diseases, such as
precocious puberty (due to mutations in luteinizing
hormone receptors) and hyperthyroidism (due to
mutations in thyroid-stimulating hormone
receptors).

19. Ligands
(Full) agonists are able to activate the receptor and
result in a maximal biological response. Most natural
ligands are full agonists.
Partial agonists do not activate receptors thoroughly,
causing responses which are partial compared to those
of full agonists.
Antagonists bind to receptors but do not activate them.
This results in receptor blockage, inhibiting the binding
of other agonists.
Inverse agonists reduce the activity of receptors by
inhibiting their constitutive activity.

20. Cell surface receptor
Cell surface receptors (membrane receptors, transmembrane
receptors) are specialized integral membrane proteins that take part in
communication between the cell and the outside world.
Extracellular signaling molecules (usually hormones,
neurotransmitters, cytokines, growth factors or cell recognition
molecules) attach to the receptor, triggering changes in the function of
the cell. This process is called signal transduction.
The binding initiates a chemical change on the intracellular side of the
membrane. In this way the receptors play a unique and important role
in cellular communications and signal transduction.

21. Types
Receptors can be roughly divided into two major
classes:
 Intracellular receptors
 Extracellular receptors.

22. Extracellular receptors
Extracellular receptors are integral transmembrane proteins and
make up most receptors. They span the plasma membrane of the
cell, with one part of the receptor on the outside of the cell and
the other on the inside. Signal transduction occurs as a result of a
ligand binding to the outside; the molecule does not pass through
the membrane. This binding stimulates a series of events inside
the cell; different types of receptor stimulate different responses
and receptors typically respond to only the binding of a specific
ligand. Upon binding, the ligand induces a change in
the conformation of the inside part of the receptor. These result
in either the activation of an enzyme in the receptor or the
exposure of a binding site for other intracellular signaling proteins
within the cell, eventually propagating the signal through the
cytoplasm.

24. These are trans membrane receptors of various types
Having 3 domains
o Extracellular Domain
oTransmembrane domain
o Intracellular domain

25. The extracellular domain
The extracellular domain is the part of the receptor that sticks out of
the membrane on the outside of the cell or organelle. If the polypeptide
chain of the receptor crosses the bilayer several times, the external
domain can comprise several "loops" sticking out of the membrane.

26. The Transmembrane Domains
In the majority of receptors for which structural evidence
exists, transmembrane alpha helices make up most of the
transmembrane domain. In certain receptors, such as the nicotinic
acetylcholine receptor, the transmembrane domain forms a protein-
lined pore through the membrane, or ion channel. Upon activation of
an extracellular domain by binding of the appropriate ligand, the pore
becomes accessible to ions, which then pass through.
In other receptors, the transmembrane domains are presumed to
undergo a conformational change upon binding, which exerts an effect
intracellularly. In some receptors, such as members of the 7TM
superfamily, the transmembrane domain may contain the ligand binding
pocket.

28. Intracellular (or cytoplasmic)
domain
The intracellular (or cytoplasmic) domain of the receptor
interacts with the interior of the cell or organelle, relaying
the signal. There are two fundamentally different ways for
this interaction:
The intracellular domain communicates via specific protein-
protein-interactions with effector proteins, which in turn
send the signal along a signal chain to its destination.
With enzyme-linked receptors, the intracellular domain
has enzymatic activity. Often, this is a tyrosine
kinase activity. The enzymatic activity can also be located on
an enzyme associated with the intracellular domain.

30. Based on structural and functional similarities, membrane receptors are
mainly divided into 3 classes:
Ion channel-linked receptor;
Enzyme-linked receptor and
G protein-coupled receptor.

31. Ion channel linked receptors
Ion channel linked receptors are ion-channels (including cation-
channels and anion-channels) themselves and constitute a large family
of multipass transmembrane proteins. They are involved in rapid
signaling events most generally found in electrically excitable cells such
as neurons and are also called ligand-gated ion channels. Opening and
closing of Ion channels are controlled by neurotransmitters.

33. Enzyme-linked receptors
Enzyme-linked receptors are either enzymes themselves, or are directly
associated with the enzymes that they activate. These are usually
single-pass transmembrane receptors, with the enzymatic portion of
the receptor being intracellular. The majority of enzyme-lined receptors
are protein kinases, or associate with protein kinases.

36. G protein-coupled receptors
G protein-coupled receptors are integral membrane
proteins that possess seven membrane-spanning
domains or transmembrane helices. These receptors
activate a G protein ligand binding. G-protein is a
trimeric protein. The 3 subunits are called α、β and γ.
The α subunit can bind with guanosine diphosphate,
GDP. This causes phosphorylation of the GDP
to guanosine triphosphate, GTP, and activates the α
subunit, which then dissociates from the β and γ
subunits. The activated α subunit can further affect
intracellular signaling proteins or target functional
proteins directly.

37. GProtein-LinkedReceptors

40. Signal transduction through membrane receptors usually requires four
characters:
Extracellular signal molecule: an extracellular signal molecule is
produced by one cell and is capable of traveling to neighboring cells, or
to cells that may be far away.
Receptor protein: the cells in an organism must have cell surface
receptor proteins that bind to the signal molecule and communicate its
presence inward into the cell.
Four Stages of Signal
Transduction

41. Intracellular signaling proteins: these distribute the signal to the
appropriate parts of the cell. The binding of the signal molecule to the
receptor protein will activate intracellular signaling proteins that initiate
a signaling cascade (a series of intracellular signaling molecules that act
sequentially).
Target proteins: the conformations or other properties of the target
proteins are altered when a signaling pathway is active and changes the
behavior of the cell.

42. Three Stages of Signal Transduction

43. Thanks