This Presentation provides an outline knowledge about Cellular Communication, Steps involved, Its Types, Signal Transduction, Secondary Messenger , Receptors with some Interesting Facts and Current Trends. An assignment for the subject, Cellular and Molecular Pharmacology, 1st year M.Pharm, 1st semester.
1. CELLULAR & MOLECULAR PHARMACOLOGY
Cell Signaling
by
Chetan A.,M.pharm 1st Year (Pharmacology)
K.K. College of Pharmacy
Chennai, Tamilnadu
2. Learning Objectives:
• Introduction
• Signal Transduction
• Steps involved in Cell Signaling
• Types of Cell Signaling
• Extracellular Signaling
• Intracellular Signaling
• Secondary Messanger
• Types of Secondary Messanger
• Current Trends
• Facts
3. CELL SIGNALING
• In order to respond to changes in their immediate environment, cells must be able to
receive and process signals that originate outside their borders.
• Cell signalling is part of any communication process that governs basic activities of
cells and coordinates all cell actions.
• The ability of cells to perceive and correctly respond to their microenvironment is the
basis of:
• -Development
• -Tissue repair
• -Immunity
• -Tissue homeostasis.
4. Continuation.,
• Errors in signaling interactions and cellular information processing are responsible
for diseases such as:
• -Cancer
• -Autoimmunity
• -Diabetes
• By understanding cell signaling, diseases may be treated more effectively and,
theoretically, artificial tissues may be created.
• Cells typically communicate using chemical signals. These chemical signals, which
are proteins or other molecules produced by a sending cell, are often secreted from
the cell and released into the extracellular space. There, they can float – like
messages in a bottle – over to neighboring cells.
6. Continuation.,
• When a signaling molecule binds to its receptor, it alters the shape or
activity of the receptor, triggering a change inside of the cell.
• Signaling molecules are often called ligands, a general term for
molecules that bind specifically to other molecules (such as receptors).
10. Continuation.,
• Cell signaling has been most extensively studied in the context of human diseases
and signaling between cells of a single organism.
• It may also occur between the cells of two different organisms.
• In many mammals, early embryo cells exchange signals with cells of the uterus.
• In the human gastrointestinal tract, bacteria exchange signals with each other and
with human epithelial and immune system cells.
• For the yeast Saccharomyces cerevisiae during mating, some cells send a peptide
signal (mating factor pheromones) into their environment.
• The mating factor peptide may bind to a cell surface receptor on other yeast cells
and induce them to prepare for mating.[9]
11.
12. SYNTHESIS OF SIGNALLING
MOLECULES
RELEASE OF SIGNALLING MOLECULES
TRANSPORT OF SIGNAL TO TARGET CELLS
DETECTION & BINDING OF SIGNAL BY SPECIFIC RECEPTOR
CHANGES DUE TO RECEPTOR- SIGNAL COMPLEX
SIGNAL REMOVAL
STEPS IN CELL SIGNALING
16. • Some common Lipid soluble messengers
• Glucocorticoids
• activatesnumerousgenesinvolvedincellular metabolism.
• Cortisol
• inhibitgeneswhoseproteinproductsare inflammatorymediators.
17. 2. PATHWAY INITIATED BY HYDROPHILIC MESSANGERS
• It is also called as Extra-cellular Signaling.
• Extracellular signalling molecules are cues, such as growth factors,
hormones, cytokines, extracellular matrix components and neurotransmitters,
designed to transmit specific information to target cells.
• Signaling by extracellular, secreted molecules can be classified into
four types.
• Paracrine
• Synaptic signaling
• Autocrine
• Endocrine
• Signaling by direct contact
18. Paracrine:
• Often, cells that are near one another communicate through the release of chemical
messengers (ligands that can diffuse through the space between the cells). This type
of signaling, in which cells communicate over relatively short distances, is known as
paracrine signaling.
• Paracrine signaling allows cells to locally coordinate activities with their neighbors.
Although they're used in many different tissues and contexts, paracrine signals are
especially important during development, when they allow one group of cells to tell
a neighboring group of cells what cellular identity to take on.
• One unique example of paracrine signaling is synaptic signaling, in which nerve
cells transmit signals. This process is named for the synapse, the junction between
two nerve cells where signal transmission occurs. (Neurotransmission)
19.
20. Autocrine:
• In autocrine signaling, a cell signals to itself, releasing a ligand that binds to
receptors on its own surface (or, depending on the type of signal, to receptors inside
of the cell). This may seem like an odd thing for a cell to do, but autocrine signaling
plays an important role in many processes.
• For instance, autocrine signaling is important during development, helping cells take
on and reinforce their correct identities. From a medical standpoint, autocrine
signaling is important in cancer and is thought to play a key role in metastasis (the
spread of cancer from its original site to other parts of the body)^66start superscript,
6, end superscript. In many cases, a signal may have both autocrine and paracrine
effects, binding to the sending cell as well as other similar cells in the area.
21.
22. Endocrine:
• When cells need to transmit signals over long distances, they often use the
circulatory system as a distribution network for the messages they send. In long-
distance endocrine signaling, signals are produced by specialized cells and released
into the bloodstream, which carries them to target cells in distant parts of the body.
Signals that are produced in one part of the body and travel through the circulation to
reach far-away targets are known as hormones.
• In humans, endocrine glands that release hormones include the thyroid, the
hypothalamus, and the pituitary, as well as the gonads (testes and ovaries) and the
pancreas. Each endocrine gland releases one or more types of hormones, many of
which are master regulators of development and physiology.
23. Continuation.,
For example, the pituitary releases growth
• hormone (GH), which promotes growth, particularly of the skeleton and
cartilage. Like most hormones, GH affects many different types of cells
throughout the body. However, cartilage cells provide one example of
how GH functions: it binds to receptors on the surface of these cells and
encourages them to divide.
24.
25. Signaling through cell-cell contact
• Gap junctions in animals and plasmodesmata in plants are tiny channels that directly
connect neighboring cells.These water-filled channels allow small signaling
molecules, called intracellular mediators, to diffuse between the two cells. Small
molecules, such as calcium ions, are able to move between cells, but large molecules
like proteins and DNA cannot fit through the channels without special assistance.
• The transfer of signaling molecules transmits the current state of one cell to its
neighbor. This allows a group of cells to coordinate their response to a signal that
only one of them may have received. In plants, there are plasmodesmata between
almost all cells, making the entire plant into onegiant network.
26.
27.
28. Receptors:
• Receptors are protein molecules inside the target cell or on its surface
that receive a chemical signal.
• There are two basic types of receptors:
• 1.Internal receptors
• 2.Cell surface receptors
29.
30.
31. Internal Receptors:
• Intracellular receptors are present inside of cell.
• Classic hormones that use intracellular receptors include thyroid and steroid
hormones.
• Examples are the class of nuclear receptors located in the cell nucleus and
cytoplasm and the IP3 receptor located on the endoplasmic reticulum.
• The ligands that bind to them are usually intracellular second messengers like
inositol trisphosphate (IP3) and extracellular lipophilic hormones like steroid
hormones.
• Some intracrine peptide hormones also have intracellular receptors.,
• Example:- Steroid hormones.
32. Cell-Surface Receptor
• Cell-surface receptors, also known as transmembrane receptors, are cell
surface, membrane-anchored, or integral proteins that bind to external
ligand molecules.
• This type of receptor spans the plasma membrane and performs signal
transduction, converting an extracellular signal into an intracellular
signal.
• Each cell-surface receptor has three main components: an external
ligand-binding domain, a hydrophobic membrane-spanning region, and
an intracellular domain inside the cell. The size and extent of each of
these domains vary widely, depending on the type of receptor.
33. Continuation.,
• Cell surface receptors can be separated into 4 categories on basis of their mechanism
of action:
-G- Protein linked receptors (GPCRs)
-Ion Channel Receptors
-Receptors lacking intrinsic catalytic activity but direct association with
cytoplasmic protein tyrosine kinase
-Receptors with intrinsic enzymatic activities
34. Ion channel-linked Receptor:
• Ion channel-linked receptors bind a ligand and open a channel through the
membrane that allows specific ions to pass through. To form a channel.
• When a ligand binds to the extracellular region of the channel, there is a
conformational change in the proteins structure that allows ions such as sodium,
calcium, magnesium, and hydrogen to pass through.
• Example. Glucose
37. Receptors with intrinsic enzymatic capacity
• GenerallyallenzymaticreceptorsareTYROSINEKINASEwithone
exceptioni.e.GUANYLYLCYCLASE
• Guanylyl cyclase catalyses the formation of cGMP(in cytosol) which in turn
actsasasecondmessengerand thenleadsto phosphorylation.
42. G-Protein Coupled:
• G-protein-coupled receptors bind a ligand and activate a membrane protein called a
G-protein. The activated G-protein then interacts with either an ion channel or an
enzyme in the membrane.
• These transmembrane receptors play a key role in the processing of odours and the
recognition of hormones.
• When a ligand binds to the GPCR it causes a conformational change in the GPCR,
which allows it to act as a guanine nucleotide exchange factor (GEF). The GPCR
can then activate an associated G protein by exchanging the GDP bound to the G
protein for a GTP. The G protein's α subunit, together with the bound GTP, can then
dissociate from the β and γ subunits to further affect intracellular signaling proteins
or target functional proteins directly depending on the α subunit type.
43.
44. Enzyme-Linked Receptor:
• Enzyme-linked receptors are cell-surface receptors with intracellular domains that are
associated with an enzyme.
• In some cases, the intracellular domain of the receptor itself is an enzyme.
• When a ligand binds to the extracellular domain, a signal is transferred through the
membrane, activating the enzyme. Activation of the enzyme sets off a chain of events
within the cell that eventually leads to a response.
45.
46. SIGNAL TRANSDUCTION:
• Signal transduction is the transmission of molecular signals from a cell's exterior to its
interior. Signals received by cells must be transmitted effectively into the cell to ensure an
appropriate response. This step is initiated by cell-surface receptors.
• There are three types
•Reception
•Transduction
•Response
• Proteins responsible for detecting stimuli are generally termed receptors.
• The changes elicited by ligand binding (or signal sensing) in a receptor give rise to a
signaling cascade, which is a chain of biochemical events along a signaling pathway.
• At the molecular level, such responses include changes in the:
• -Transcription or translation of genes
• -Post-translational and conformational changes in protein
• -Changes in proteinlocation.
47. Continuation.,
• Reception: A cell detects a signaling molecule from outside of the cell. A
signal is detected when the chemical signal (also known as a ligand)
binds to a receptor protein on the surface of the cell or inside the cell.
• Transduction: When the signaling molecule binds the receptor it
changes the receptor protein in some way. This change initiates the
process of transduction. Signal transduction is usually a pathway of
several steps. Each relay molecule in the signal transduction pathway
changes the next molecule in the pathway.
• Response: Finally, the signal triggers a specific cellular response.
50. Secondary Messanger
• Secondary messengers are intracellular
signaling molecules realeased by the
cell to trigger physiological changes
such as proliferation, differentiation,
migration, servival, and apoptosis.
• Second messengers and there one of the
initiating components of intracellular
signal transduction cascades.
• Example of secondary messengers
include cycle AMP, cyclic GMP, Inositol
triphosphate, Diacylglycerol and
Calcium.
52. Intracellular Signaling
• Intracellular signaling is an important mechanism by which cells can respond to their
environment and extracellular cues. Cells can sense their environment and modify
gene expression, mRNA splicing, protein expression and protein modifications in
order to respond to these extracellular cues.
53. cAMP Cyclic adenosine monophosphate
• Cyclic adenosine
monophosphate (cAMP, cyclic
AMP) is a second messenger
important in many biological
processes. cAMP is a
derivative of adenosine
triphosphate (ATP) and used
for intracellular signal
transduction in many different
organisms.
54. cGMP Cyclic guanosine monophosphate
• Cyclic guanosine monophosphate
(cGMP) is a cyclic nucleotide
derived from guanosine
triphosphate (GTP). cGMP acts as
a second messenger much like
cyclic AMP. Its most likely
mechanism of action is activation
of intracellular protein kinases in
response to the binding of
membrane- impermeable peptide
hormones to the external cell
surface. Its roles are not as clearly
understood.
55. 1. VISUALIZING CELL SIGNALLING
• Techniques for the study of intracellular ions are used widely in biology, including for the
tracking of calcium waves or ions affecting pH within living cells.
• The ability to monitor changes in intracellular ion concentrations over time is vital
• Ion channels that span the outer cell membrane open or close in response to
extracellular and intracellular signals, potentially altering how the cell behaves.
• These fluctuations can be visualized and quantified using ratiometric microscopy and
special fluorescent dyes designed to bind specific ions, such as the FURA-2 indicator dye
specific to calcium ions.
• Changes in the photophysics of the dye as it binds to its target ion allows for
quantitation of the bound and unbound ratio, and thus the concentration of the ion
under investigation.
CURRENT TRENDS
56. • GFP-based kinase reporters that phase-separate upon kinase activation via multivalent
protein-protein interactions, forming intensively fluorescent droplets. Called SPARK
(separation of phases-based activity reporter of kinase)
• These reporters have large dynamic range (fluorescence change), high brightness, fast
kinetics, and are reversible. The SPARK-based protein kinase A (PKA) reporter
reveals oscillatory dynamics of PKA activities upon G protein- coupled receptor
activation.
• The SPARK-based extracellular signal-regulated kinase (ERK) reporter unveils
transient dynamics of ERK activity during tracheal metamorphosis in live
Drosophila.
• Because of intensive brightness and simple signal pattern, SPARKs allow easy
examination of kinase signaling in living animals in a qualitative way. The modular
design of SPARK will facilitate development of reporters of other kinases.
CURRENT TRENDS
57. 2. STEM CELLS
• Stem cells are undifferentiaied cell that can differentiate and give rise to different kind
of cells.
• Stem cells are responsible for proper development of body, tissue repair and
growth.
• These cells are complicated in types of cancers
• They have unlimited potential to cure many diseases
• IPSC's are induced pluripotent stem cell that are artifically created from
differentiated cell by dedifferentiation
• IPSC's are used to treat tissue disorders, cataract and other diseases,
• Cell signals that maintain stemness of a factor are being extensively studied.
CURRENT TRENDS
58. • Cytokine-dependent activation of STAT3 drives ES cell self-renewal
• ERKs antagonize ES cell self-renewal
• PI3K signalling in ES cell propagation
• An increased amount of 3′-phosphorylated phosphoinositides is frequently
associated with growth factor and cytokine signalling pathways.
• Unique signalling adaptors in ES cells
-Embryonic stem cells express a variant of SH2-containing inositol 5′-
phosphatase (SHIP) that lacks the SH2 domain This enzyme normally removes
5′ phosphates from the lipid products of PI3K, and in some systems it inhibits
the activation of downstream signals such as PKB.
-Embryonic stem cells also specifically express large amounts of a variant Gab1
molecule. This protein lacks the N-terminal PH domain, which results in attenuated
coupling to the Ras/ERK cascade .
• Cell-cycle control differs in differentiated cells and ES cells
CURRENT TRENDS
59.
60. Facts
• Cyclic AMP (cAMP) is a common second messenger involved in signal
transduction cascades, it was the first second messenger ever discovered.
• Not all cells can “hear” a particular chemical message. Its needs specific
receptors to bind.
• In bacteria and other single-cell organisms, the transduction processes a
cell has limits the number of ways it can respond to its environment.
• In multicellular organisms, lots of different signal transduction processes
are used to coordinate the behavior of individual cells.
62. ~Quote~
~”We don’t even celebrate our success more than a day, then why we cry on
our problems for more than a day?”
~”Do the opposite thing, Either enjoy your happiness more than it deserves
or cry for your worries not more than it deserves.”
