Cell Signaling | Steps Involved | Types | Receptors | Signal Transduction | Intracellular & Extracellular Signaling | Secondary Messanger

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 1 st 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.

5. What happens in Cell Signaling ?

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).

7. Figure 1

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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. SYNTHESIS OF SIGNALLING MOLECULES RELEASE OF SIGNALLING MOLECULES TRANSPORT OF SIGNAL TO TARGET CELL S DETECTION & BINDING OF SIGNAL BY SPECIFIC RECEPTOR CHANGES DUE TO RECEPTOR- SIGNAL COMPLEX SIGNAL REMOVAL S T E P S IN CELL SIGNALING

12. Extra-Cellular Signaling Inter-Cellular Signaling Secondary Messanger

13. Some common Lipid soluble messengers Glucocorticoids activates numerous genes involved in cellular metabolism. Cortisol inhibit genes whose protein products are inflammatory mediators.

14. 2. PATHWAY INITIATED BY HYDROPHILIC MESSANGERS It is also called as Extra-cellular Signaling. Extracellular signalling molecules are cues, such as growth factors, h o r m o n es , cyt o ki n es, extracellular m atrix c o m p o nen t s and neur o tran sm itters, d e si g n e d to trans m it specific infor m ation to ta r get cells. Si g na l i n g b y extracell u la r , secret e d m o l e c u l es ca n b e clas s ified in t o four types. Paracrine Synaptic signaling Autocrine Endocrine Signaling by direct contact

15. 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)

16. 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.

17. 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.

18. 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 .

19. 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 one giant network.

20. 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

21. 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.

22. 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.

23. 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

24. Ion channel-linked Receptor: Ion channel-linked receptors bind a ligand and open a channel through t h e m e m b rane t h at allows s p e cific i o ns to pass t hro u g h . T o f o rm 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

25. Ligand Gated Ion Channel Receptor protein acts as an ion channel Seen in; Nerve-nerve junctions Neuro -muscular junctions

26. Receptors with intrinsic enzymatic capacity Generally all enzymatic receptors are TYROSINE KINASE with one exception i.e. GUANYLYL CYCLASE Guanylyl cyclase catalyses the formation of cGMP (in cytosol ) which in turn acts as a second messenger and then leads to phosphorylation .

27. Cytokines receptors There are regulatory proteins These receptors does not have any enzymatic activity of their own but their enzymatic action lies in a family of separate cytoplasmic kinases . Cascade of phosphorylation leads to cellular response to stimulus Mainly involves the Immune system

28. 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.

29. 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.

30. 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 .

31. 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. T ran s d u ct i o n : W hen t h e sign a li n g m o l ecule b i nds t h e r e c e p t or it changes t he rec e p t or p r o t ein i n s o m e w a y . This change ini t iates t he p r ocess of trans d uc ti o n . Si g nal trans d uc ti on is us u a lly a path w ay 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.

32. Figure 4

33. Secondary Messanger Secondary messengers are intracellular signaling molecules realeased by the cell to trigger physiological changes such as proliferation, differentiation, migration, servival, and apoptosis. S econd 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.

34. Continuation.,

35. 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.

36. 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.

37. 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.

38. 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

39. 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

40. 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

41. 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

42. Facts C yclic 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.

43. REFERENCES Wikipedia Internet URL Slideshare Khan Academy

44. ~ 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.”

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