Cell signaling Part-1

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1. What is cell signaling? • All cells receive and respond to signals from their surroundings • Communication between cells. Hormone Growth factor Cytokine Steroid Polypeptide Signal from where? The ligand is the signaling molecule. ligand may be Signaling molecules, which are released by signal-producing cells, reach and transfer biological signals to their target cells to initiate specific cellular responses

2. CONDITION FOR SIGNALING Receptor activated by ligand, the receptor causes a change in the target cell in which it is expressed Extracellular molecules Protein, peptides, Hormone, cytokine adrenaline, thyroxine . prostaglandin Intracellular molecules   C Ca2 +, carbohydrate, CAMP/CGMP Intercellular signaling Communication between cells Intracellular signaling   Signaling chains within the cell

3. Intercellular signalling Controls Metabolic fluxes Cell division Growth Development Processes sensory information Differentiation Cells communicate via Messenger substances Gap junctions Surface proteins Electrical signals

4. Hormones As a Signal molecules Binding with Receptor Activated Enzyme Second messenger Transcription Effect on cellular function Extracellular Intra cellular Ankit Mishra

5. The signalling molecules produce an effect on same cell that produce it Autocrine signalling Autocrine signalling the cell that is producing the messenger expresses receptors on its surface that can respond to that messenger Consequently , cells releasing the message will stimulate (or inhibit) themselves.

6. The cytokine interleukin-1 in monocytes. When interleukin-1 is produced in response to external stimuli, it can bind to cell-surface receptors on the same cell that produced it. Activated T lymphocytes T lymphocyte respond to antigenic stimulation by synthesizing a growth factor that derives their own proliferation, and there by increasing the number of responsive T-Lymphocytes Cancer development- Autocrine signaling plays critical roles in cancer activation and also in providing self-sustaining growth signals tumors EXAMPLES OF AUTOCRINE SIGNALING

7. •Paracrine signaling is a form of cell-to-cell communication in which a cell produces a signal to induce changes in nearby cells(close proximity ) • Signaling molecules known as paracrine factors diffuse over a relatively short distance   ( local action ) • Cells that produce paracrine factors secrete them into the Immediate extracellular environment . • Follow paracrine signaling pathway-Fibroblast family, Hedgehog family, Wnt family, and TGF-B superfamily. Growth Factor(FGF) Receptors available on the cell membrane to receive the signals, also known as Being competent PARACRINE SIGNALING

8. • The signaling molecule act on target cells distantly located from the Site of synthesis . • It is a long range signaling and signal molecules is transported by   Blood streams .   The pancreas is an endocrine gland and produces the hormone insulin, which regulates the uptake of glucose in cells all over the body.   Hormones that function in an endocrine manner include testosterone, progesterone and gonadotropins. ENDOCRINE SIGNALING EXAMPLES OF ENDOCRINE SIGNALING

9. JUXTACRINE SIGNALING • This kind of signaling require physical contact between the cells. Also known as contact-dependent signaling. A membrane ligand (protein, oligosaccharide, lipid) and a membrane protein of two adjacent cells interact. A communicating junction links the intracellular compartments adjacent cells, allowing transit of relatively small molecules. An extracellular matrix glycoprotein and a membrane protein interact. 3 types of juxtacrine signaling molecules.

10. TYPES OF LIGANDS Membrane bound signal molecule – signal molecule remain surface of the cell and mediate contact dependent signaling. 2. Secretory signal molecules- secreted from signaling cell and binds to receptor. Secretory signal molecules are extracellular and divided in 3 categories depending on distance 1 2 3 Endocrine Paracrine Autocrine Depending On The Nature Of Extracellular Signal Molecules It Is Divided In 2 More Categories LIPOPHILIC MOLECULES HYDROPHILIC MOLECULES

11. EXAMPLE OF SIGNAL MOLECULES THAT INTRACT WITH CELL SURFACE RECEPTOR Epinephrine Glucagon Insulin Gastrin Secretin Adrenocorticotropic hormone

12. EXAMPLE OF SIGNAL MOLECULES THAT INTRACT WITH CYTOSOLIC OR NUCLEAR RECEPTOR Steroid hormones- Progesterone, testosterone, cortisol, aldosterone. Non steroid hormones- thyroid hormone and retinoic acid.

13.   • Receptors are protein molecules inside the target cell or on its surface that receive a chemical signal . • Chemical signals are released by signaling cells in the form of small, or soluble molecules called ligands. RECEPTOR AND LIGAND Orphan receptor Orphan receptor is a protein that has a similar structure to other identified receptors but whose ligand has not yet been identified.

14. Intracellular receptors Intracellular receptors are receptor proteins found on the inside of the cell, typically in the cytoplasm or nucleus. The ligands of intracellular receptors are small, hydrophobic{water hating) molecules, since they must be able to cross the plasma membrane in order to reach their receptors. For example, receptors for hydrophobic steroid hormones, such as the sex hormones -an oestrogen and testosterone, thyroid hormone, retinoid and vitamin D are intracellular. Also contain orphan receptors.

15. Intracellular receptors Intracellular receptor belongs to Nuclear receptor superfamily Nuclear receptor superfamily is a family of highly conserved transcription factors that regulates transcription in response to small lipophilic signal molecules. Members of the Nuclear receptor superfamily can both positively and Negatively regulate transcription .

16. Nuclear receptor superfamily N-terminal activation domain, called the A/B region, A central DNA binding domain(DBD) and A C-terminal ligand binding domain (LBD)

17. Example Steroid hormone receptor Location-cytosol Homodimer receptor In cytosol= receptor + HSP - INACTIVE In cytosol= receptor+ligand receptor-ligand complex • It can be homodimer-example ----steroid receptor • It can be heterodimer- example--- retinoic acid receptor, thyroid hormone receptor, vitamin D receptor and orphan receptor Nuclear receptor Thyroid hormone receptor Heterodimer receptor Location of receptor= nucleus

18. Cell-surface receptors Cell-surface receptors, also known as transmembrane receptors, are proteins that are found attached to the cell membrane. These receptors bind to external ligand molecules because ligands do not travel across the cell membrane. This type of receptor spans the plasma membrane and performs signal transduction, in which an extracellular signal is Converted into an intercellular signal. Cell-surface receptors are also called cell-specific proteins or markers because they are specific to individual cell types.

19. Cytosol • Each cell-surface receptor has three main components : 1. An external ligand-binding domain 2. A hydrophobic membrane-spanning region, and 3. An intracellular domain inside the cell. Cell-surface receptors

20. Dimerization 2. Conformational changes Mechanism of working Categories of cell-surface receptors Ion channel-linked receptors, G-protein-linked receptors, and Enzyme-linked receptors.

21. Ion channel linked receptors Also called transmitter gated ion channel or inotropic receptors. lon channel-linked receptors bind a ligand and open a channel through the membrane that allows specific ions to pass through. To form a channel, this type of cell-surface receptor has an extensive membrane-spanning region. When a ligand binds to the extracellular region of the channel, there is a conformational change in the proteins structure

22. Example- ligand gated channel for NTMs- Acetycholine • Acetylcholine receptor is a receptor linked to a cation channel .   • As two molecules of acetylcholine bind to the binding sites on a subunits, the conformation of the receptor is altered and the gate is opened, allowing for the entry of many ions and small molecules.

23. G-protein-coupled receptors It is a G-protein linked receptor G-protein-coupled receptors bind a ligand and activate a membrane protein called a G-protein. The activated G-protein then interacts with an enzyme in the membrane Before the ligand binds, the inactive G-protein can bind to a site on a specific receptor. Once the G-protein binds to the receptor, the G-protein changes shape, becomes active, and splits into two different subunits. One or both of these subunits may be able to activate other proteins as a result.

24. G- Protein Coupled Receptor

25. Enzyme-linked receptors 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. Other enzyme-linked receptors have a small intracellular domain that interacts directly with 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

26. G-PROTEIN LINKED RECEPTOR What is GPCR? What is G Protein and its mode of action? What is GTP? What is GTPase? What is GEF(Guanine exchange factor)? What is stimulatory G-protein? What is secondary messenger?

27. What is GPCR? G-Protein coupled receptor(GPCR) or G-Protein linked receptor. Have seven transmembrane domain, so it is also called serpentine Extracellular receptor. Largest family of cell surface receptor. Multiple single polypeptide. GPCR present is all eukaryotes GPCR are the largest group of cell surface receptor that transmit signal inside the cell with the action of guanine nucleotide binding protein called G-protein.

28. What is G Protein? G proteins, also known as guanine nucleotide-binding proteins, are a family of proteins that act as molecular switches inside cells, and are involved in transmitting signals from outside a cell to its interior. G proteins belong to the larger group of enzymes called GTPases. What is GTPase? GTPases are large family a of hydrolase enzymes that can bind and hydrolyze guanosine Triphosphate (GTP) What is GTP? It also has the role of a source of energy or an activator of substrates in metabolic reactions, like that of ATP. GTP is essential to signal transduction, with G-proteins. It is converted to guanosine diphosphate (GDP) through the action of GTPases.

29. Mode of Action The inactive form of GTPase (GDP) are activated by a class of protein called guanosine nucleotide exchange factor (GEFs)

30. GPCR has receptors for NTMS Neuropeptides   Peptide hormone Immune cells Disease factors Adrenaline ( epinephrine) Smell Light Taste

31. What is stimulatory G- Protein When G- protein involved in activation of enzyme like effector, Adenylate cyclase, is called stimulatory G-protein

32. What is Primary messenger? Ligand are termed as primary/first messengers. First messengers are extracellular factors, often hormones, Growth Factor , neurotransmitters, Peptides etc. What is secondary messenger? Second messengers are intracellular signaling molecules released by the cell in response to exposure to extracellular signaling molecules – the first messengers. They triggers intracellular signal transduction cascades.

33. Removal or degradation of second messenger terminate the cellular response Four classes of second messengers Cyclic nucleotides Membrane lipid derivatives Ca2+ Nitric oxide/carbon monoxide Examples of second messenger molecules include cyclic AMP, cyclic GMP, inositol trisphosphate (IP3), diacylglycerol , and calcium

34. Which of the following is NOT a second messenger ? 1. Cyclic GMP   2. Diacylglycerol   3. Inositol triphosphate 4. Phosphatidyl inositol

35. G-protein coupled receptors (GPCR) consist of three protein subunits a. B and y. In unstimulated state, a subunit is GDP bound and GPCR is inactive. When GPCR gets activated, it acts like guanine nucleotide exchange (GEF) factor and induces a-subunit to release its bound GDP allowing GTP to bind in its place. In order to regulate G protein activity by regulating GDP/GTP concentration, a subunit acts as GTPase   GDP kinase   CGMP-specific phosphodiesterase   CAMP-specific phosphodiesterase