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Cell Signalling and Secondary messengers
- 1. SECONDARY MESSENGERS AND INTRACELLULAR SIGNALING PATHWAYS A.Venkatraman M Pharm 1styear 1st semester Pharmacology 1
- 2. DIFFERENCE BETWEEN PRIMARY AND SECONDARY MESSENGERS PRIMARY MESSENGER Extracellular factors like hormones, or neurotransmitters such as epinephrine, growth hormones and serotonin PEPTIDE HORMONES and neurotransmitters are hydrophilic Physically cannot cross the phospholipids bilayer SECONDARY MESSENGER These are intermediate molecules like cyclic AMP or cyclic GMP When hormones bind to the target cell receptor, the cell release or creates this intermediates which then stimulate cell responses Pathway involve SIGNAL TRANSDUCTION PATHWAYS
- 3. SECONDARY MESSENGERS: Secondary messengers are molecules that relay signals from receptors on the cell surface to target molecules inside the cell They greatly amplify the strength of the signal ,cause some kind of change in the activity of the cell They are a component of cell signaling pathways EARL WILBUR SUTHERLAND jr., discovered secondary messengers, for which he won the 1971 Nobel prize 3
- 4. IMPORTANCE OF SECONDARY MESSENGERS Short lived intracellular signaling molecules Elevated concentration of secondary messengers leads to rapid alteration in the activity of one or more cellular enzymes Removal or degradation of secondary messengers terminate the cellular response Four classes of secondary messengers include Cyclic nucleotides Membrane lipid derivatives Ca2+ Niric oxide or carbon monoxide 4
- 5. TYPES OF SECONDARY MESSENGERS 5
- 6. CAMP SIGNALING PATHWAY CAMP, a major target of G-Protein signaling in mammalian cells discovered in 1958 by earl sutherland Sutherland found that the action of epinephrine was mediated by an increase in the intracellular concentration of cAMP, leading to the concept that cAMP is a second messenger in hormonal signaling cAMP is formed from ATP by the action of adenylyl cyclase which is stimulated by Gs and degraded to AMP by cAMP phosphodiesterase 6
- 7. BASIC CONCEPT Effects of cAMP in animal cells are mediated by the action of cAMP dependent protein kinase, or protein kinase A Protein kinase A is a tetramer consisting of two regulatory and two catalytic subunits. Cyclic AMP binds to the regulatory subunits, leading to their dissociation from the catalytic subunits. The free catalytic subunits are then enzymatically active and able to phosphorylate serine residues on their target proteins 7
- 8. Regulation of glycogen metabolism by epinephrine Receptor stimulation by epinephrine leads to G protein mediated activation of adenylyl cyclase. cAMP activates protein kinase A, which consists of two regulatory (R) and two catalytic (C) subunits in its inactive form. Binding of cAMP to the regulatory subunits induces a conformational change that leads to dissociation of the catalytic subunits, which are then enzymatically active. Protein kinase A activates phosphorylase kinase and phosphorylase kinase activates glycogen phosphorylase, which catalyzes the breakdown of glycogen to glucose1phosphate. 8
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- 10. Cyclic AMP-inducible gene expression Receptor stimulation leads to G protein mediated activation of adenylyl cyclase, synthesis of cAMP, and activation of protein kinase A. The free catalytic subunit of protein kinase A translocates to the nucleus and phosphorylates the transcription factor CREB [ CRE binding protein] It leads to the recruitment of coactivators and expression of cAMP inducible genes cAMP plays important roles in controlling Proliferation Survival Differentiation of wide variety of animal cells Learning and memory 10
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- 12. Regulation of protein phosphorylation by protein kinase A and protein phosphatase 1 Protein phosphorylation is rapidly reversed by the action of protein phosphatases These protein phosphatases serve to terminate the responses initiated by receptor activation of protein kinases. EXAMPLE ;the serine residues of proteins that are phosphorylated by protein kinase A are usually dephosphorylated by the action of a phosphatase called protein phosphatase 1 The levels of phosphorylation of protein kinase A substrates (such as phosphorylase kinase and CREB) are thus determined by a balance between the intracellular activities of protein kinase A and protein phosphatases. 12
- 13. EFFECTS OF cAMP cAMP are mediated by protein kinase A CAMP as a secondary messenger involved in sensing smells The odorant receptors in sensory neurons in the nose are G protein-coupled receptors that stimulate adenylyl cyclase, leading to an increase in intracellular cAMP. cAMP in this system directly opens Na+ channels in the plasma membrane, leading to membrane depolarization and initiation of a nerve impulse. 13
- 14. CGMP AS SECONDARY MESSENGER: It is an important messenger in animal cell Cyclic GMP is formed from GTP by guanyl cyclase and degraded to GMP BY phosphodiesterase Guanyl cyclase are activated by nitric oxide and carbon monoxide as well as peptide ligands Stimulation of these guanyl cyclase leads to elevation level of cGMP which mediate responses such as blood vessel dilation The action of cGMP is activated is mediated by the activation of cGMP- dependent protein kinases. It also regulates ion channels and phosphodiesterases Nitric oxide stimulates the synthesis of cGMP 14
- 15. ROLE OF cGMP IN PHOTORECEPTION 15 It is responsible for converting the visual signals received as light to nerve impulses The photoreceptor in rod cells of the retina is a G-protein coupled receptor called RHODOPSIN Absorption of light by retinal activates the G-protein coupled receptor RHODOPSIN. The alpha subunit of Transducin then stimulates cGMP phosphodiesterase ,leading to a decrease in intracellular levels of cGMP This change in cGMP levels in retinal rod is translated to a nerve impulse by direct effect of cGMP in ion channels.
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- 17. Ca2+ a secondary messengers Many cells respond to extracellular stimuli by altering their intracellular calcium concentration Ca++ acts as secondary messenger in two ways: It binds to an effector molecule such as an enzyme ,activating it; It binds to an intermediary cytosolic calcium binding protein such as CALMODULIN The binding of ca++ causes profound conformational changes in calmodulin that increase calmodulin's affinity for its effector molecules Calmodulin ,when activated causes contraction of smooth muscles. 17
- 19. NITRIC OXIDE(N0) Nitric oxide (NO) acts as a secondary messenger because it is free radical that can diffuse through the plasma membrane and affect nearby cells It is synthesized from arginine and oxygen by the NO synthase It activates soluble guanyl cyclase, which when activated produces another secondary messenger, cGMP It is toxic in high concentration, but is the cause of many other function like relaxation of blood vessels, apoptosis.
- 21. PHOSPHATIDYLINOSITOL-DERIVED SECONDARY MESSENGERS Phosphatidylinositol(PI) is a negatively charged phospholipid and a minor component in eukaryotic cell membranes. The inositol can be phosphorylated to form 1. Phosphatidylinositol-4-phosphate(PIP) 2. Phosphatidylinositol-4-5-bis-phosphate(PIP3) 3. Phosphatidylinositol-3,4,5-triphosphate(PIP3) Intracellular enzyme PHOSPHOLIPASE C (PLC) hydrolyzes PIP2 which is found in the inner layer of the plasma membrane . It yields two products 1. Diacylglycerol(DAG) 2. Inositol-1,4,5-triphosphate(IP3)
- 23. DIACYLGLYCEROL Diacylglycerol stimulates protein kinase C activity by greatly increasing the affinity of the enzyme for calcium ions Protein kinase C phosphorylates specific serine and threonine residues in target proteins. Known target proteins include calmodulin, the glucose transporter, HMG-CoA reductase, cytochrome P450
- 24. INOSITOL TRIPHOSPHATE(IP3) This soluble molecule diffuse through the cytosol and binds to receptors on the endoplasmic reticulum causing the release of calcium ions into the cytosol The rise in intracellular calcium triggers the response Example ; the calcium rise is needed for NF-AT (the "nuclear factor of activated t cells") to turn on the appropriate genes in the nucleus
- 25. Phospholipase C: IP3-DAG pathway Activation of phospholipase Cβ (PLcβ) by the activated GTP carrying α subunit of Gq hydrolyses the membrane phospholipid phosphatidyl inositol 4,5- bisphosphate (PIP2) to generate the second messengers inositol 1,4,5- trisphosphate (IP3) and diacylglycerol (DAG). The primary action of IP3 is facilitation of Ca2+ mobilization from intracellular organellar pools While DAG in conjunction with Ca2+ activates protein kinase C (PKc) which phosphorylates and alters the activity of a number of functional and structural proteins Cytosolic Ca2+ is a veritable messenger: combines with calmodulin (CAM) to activate myosin light chain kinase (MLCK) inducing contraction, and another important regulator calcium-calmodulin protein kinase (CCPK).
- 28. MITOGEN ACTIVATED PROTEIN KINASE(MAPK) SIGNALING The MAP kinase pathway refers to a cascade of protein kinases that are highly conserved in evolution and play central roles in signal transduction in all eukaryotic cells ranging from yeasts to humans. MAPK is an enzyme that translocates signals to nucleus and activates many transcriptional factors It phosphorylates many different protein that regulates expression of cell cycle The importance of Ras in intracellular signaling was then indicated by experiments showing that active Ras directly induces proliferation of normal mammalian cells.
- 29. Regulation of Ras proteins
- 31. Induction of immediate-early genes by ERK
- 32. JAK STAT SIGNALING PATHWAY The kinases associated with cytokine receptors include members of the Janus kinase (or JAK) family, which consists of four related nonreceptor tyrosine kinases. The key targets of the JAK kinases are the STAT proteins (signal transducers and activators of transcription) Stimulation of cytokine receptors leads to recruitment of STAT proteins, which bind via their SH2 domains The STAT proteins are phosphorylated by JAK family kinases. Pairs of phosphorylated STAT dimerize and translocate to the nucleus to regulate gene transcription resulting in a biological response. Many cytokines, growth hormone, prolactin, interferons, etc. act through this type of receptor.
- 33. The STAT proteins are transcription factors with SH2 domains that mediate their binding to phosphotyrosine containing sequences. In unstimulated cells, STAT proteins are inactive in the cytosol. Stimulation of cytokine receptors leads to the binding of STAT proteins to phosphotyrosine binding sites on the receptor, where they are phosphorylated by the receptor associated JAK tyrosine kinases. The phosphorylated STAT proteins then dimerize and translocate to the nucleus, where they activate the transcription of target genes
- 34. CONCLUSION Signal transduction pathways allows cell to respond to environmental signals In these pathways signals are amplifies This signal amplification is brought by secondary messengers like cAMP ,cGMP, Ca ions,IP3,DAG,NO Secondary messengers essentially serve as chemical relays from the plasma membrane to the cytoplasm thus carrying intracellular signaling pathways .
- 35. REFERENCES The Cell, A Molecular Approach. Geoffrey M Cooper, eighth edition,2019 KD. Tripathi. Essentials of Medical Pharmacology, Seventh edition The Pharmacological Basis of Therapeutics, Goodman and Gillman‘s Karp, Gerald, cell and molecular biology, sixth edition, john Wiley and sons, inc.