Cell Signalling Pathways PDF

Biol111: Cellular Biology and Biochemistry Lecture 35 Cell Signalling Pathways  Cellular Signalling For any given cell: hundreds of different signals it can respond to, hundreds of different receptors, thousands of different pathways that can be activat...

Biol111: Cellular Biology and Biochemistry Lecture 35 Cell Signalling Pathways  Cellular Signalling For any given cell: hundreds of different signals it can respond to, hundreds of different receptors, thousands of different pathways that can be activated leading to lots of different responses. Aims of these lectures: We won’t go into specific details on any specific signalling pathways Instead want to go over the major themes of cell signalling Pathways involved in cell death  2. Kinds of signalling +through cell junctions  2. Kinds of signalling 3. Long-distance signalling Called endocrine signalling Mediated by hormones  2. Kinds of signalling 3. Long-distance signalling Called endocrine signalling Mediated by hormones  2. Kinds of signalling Signalling molecules can be Gaseous, water-soluble, lipid-soluble Small molecules or proteins Ethylene, gas Estrogen, lipid-soluble Insulin, a protein Signal transduction pathways 1. Signal reception binding of a signal to a receptor protein 2. Signal transduction relay of molecules within cell. 3. Signal response change in protein activity or expression.  3. Reception of signals A signalling molecule binds to a receptor and it changes shape. Receptors are specific for certain signals So that only the correct cells respond “lock and key” So that the cells don’t respond to the wrong signals A ligand is the specific signalling molecule that binds to a specific receptor Signal reception - Signal transduction - Signal response  3. Reception of signals Receptors: Cell-surface receptors: i. Ligand-gated ion channel receptors. ii. G protein-coupled receptors. iii. Enzyme-coupled receptors Cytoplasmic receptors: iv. Steroid receptors 30% of human proteins are cell surface receptors! Signal reception - Signal transduction - Signal response Ligand-Gated Ion Channel Receptors System involves: * signal molecule (wide range possible). * gated ion channel. When the signalling molecule binds to the channel, it opens and allows the flow of specific ions. It is critical that the gate returns to the closed position at the end of the signal. Reece et al. (2011) Campbell Biology, 9th ed, Fig. 11.07 Ligand-Gated Ion Channel Receptors Example: chemical synapses Ligand: neurotransmitter eg. Dopamine, acetyl choline Receptor: Transmitter-gated ion channel Effect: activation of the next nerve cell by ions entering the cell Alberts et al. (2014) Molecular Biology of the Cell, Fig. 11.36  II. G Protein-Coupled Receptors (GPCRs) G protein receptors are signal receptors found associated with the plasma membrane. Found in all eukaryotes. 800 different GPCRs in humans 60% of drugs target GPCR pathways Reece et al. (2011) Campbell Biology, 9th ed, Fig. 11.07  G Protein-Coupled Receptors System involves: signal molecule (ligand) G protein-coupled receptor G protein enzyme. Reece et al. (2011) Campbell Biology, 9th ed, Fig. 11.07  II. G Protein-Coupled Receptors (GPCRs) G proteins are GTP-binding proteins Inactive G-protein  ATP  GTP Active G-protein  GDP Reece et al. (2011) Campbell Biology, 9th ed, Fig. 11.07  G Protein-Coupled Receptors System involves: The signal molecule binds to the signal molecule (ligand) receptor. G protein-coupled receptor Receptor shape changes to allow G protein G-protein to bind enzyme. G protein is activated by switching GDP for GTP 1. Resting state 2. GPCR activates G-protein Reece et al. (2011) Campbell Biology, 9th ed, Fig. 11.07  G Protein-Coupled Receptors Activated G-protein then G protein deactivated by activates an enzyme that hydrolysis of GTP to GDP. triggers a cellular response Signalling system turned off and reset. 3. G-protein activates enzyme 4. System returns to resting state Reece et al. (2011) Campbell Biology, 9th ed, Fig. 11.07  G Protein-Coupled Receptors Examples: Adrenaline receptor Rhodopsin: photoreceptor Reece et al. (2011) Campbell Biology, 9th ed, Fig. 11.07  Signal transduction pathways 1. Signal reception Signal transduction Receptors: usually pathways can involve only found in the plasma proteins membrane eg. phosphorylation cascades Or they might involve 2. Signal small molecules transduction Second messengers Second messengers or signalling proteins Why have multiple steps? Amplification Control 3. Signal response Multiple responses Effectors  5. Second messengers The “first messenger” = extracellular signalling molecule. The “second messenger” is produced or activated within cell following receptor activation. The second messenger carries the signal into the cell. Second messengers are small signalling molecules produced within cells. They transduce external signals into internal responses. Examples of signal transduction molecules A small molecule: Calcium A protein: Kinases Signal reception - Signal transduction - Signal response Second messenger: Calcium Calcium concentrations in the extracellular space are high (mM) Calcium concentrations in certain organelles are also high: mitochondria, endoplasmic reticulum. Calcium needs to be continually pumped from the cytoplasm outside of the cell or into organelles. Reece et al. (2011) Campbell Biology, 9th ed, Fig. 11.13  Calcium How does calcium act as a second messenger? by causing direct effects such as neurotransmitter release and muscle contraction by binding to specific proteins such as calmodulin which then activate further proteins. Calcium triggers release of vesicles Alberts et al (2004) Molecular Biology of the Cell 4th ed. Fig. 15.40 Calcium In relaxed muscle, the thick and thin filaments are widely spaced A calcium trigger and ATP results in muscle contraction. Lodish et al (2008) Molecular Cell Biology, 6th ed. Fig. 17.30  Calcium Calcium triggers movement of the tropomyosin filament. Movie:https://www.youtube.com/watch?v=eyYTHn2JLgI Lodish et al (2008) Molecular Cell Biology, 6th ed. Fig. 17.30  Calcium How does calcium act as a second messenger? by causing direct effects such as muscle contraction and neurotransmitter release by binding to specific proteins such as calmodulin which then activate further proteins. Calmodulin becomes active when its shape changes and binds to other proteins Alberts et al (2004) Molecular Biology of the Cell 4th ed. Fig. 15.40 6. Transduction - Phosphorylation Cascades phosphorylation - addition of a phosphate group. kinase - an enzyme that adds a phosphate group. phosphorylation acts as an on/off switch to a protein 5. Transduction - Phosphorylation Cascades phosphorylation - addition of a phosphate group. kinase - an enzyme that adds a phosphate group. phosphorylation acts as an on/off switch to a protein Transduction - Phosphorylation Cascades A signalling molecule binds to a plasma membrane receptor protein. Reece et al. (2011) Campbell Biology, 9th ed, Fig. 11.10 Transduction - Phosphorylation Cascades A protein kinase is activated by the relay molecule. Reece et al. (2011) Campbell Biology, 9th ed, Fig. 11.10 Transduction - Phosphorylation Cascades This third protein kinase activates target proteins which generate a cellular response. Reece et al. (2011) Campbell Biology, 9th ed, Fig. 11.10 Transduction - Phosphorylation Cascades The entire pathway is called a phosphorylation cascade. Cascades are common in signalling pathways and allow for amplification. Reece et al. (2011) Campbell Biology, 9th ed, Fig. 11.10 Transduction - Phosphorylation Cascades The The entire activated pathway protein is called kinaseacan phosphorylation be cascade. deactivatedCascades by a are common phosphatase. in signalling The pathways pathway canandbeallow for amplification. deactivated. Reece et al. (2011) Campbell Biology, 9th ed, Fig. 11.10  Transduction - Amplification Amplification allows a small initial signal to be massively increased. Example: * 1 molecule of epinephrine binds a G protein-coupled receptor. * 100 or more activated G proteins. * 1000 molecules of cAMP. * 1 million activated molecules of glycogen phosphorylase. * 100 million molecules of glucose-1-phosphate. Reece et al. (2011) Campbell Biology, 9th ed, Fig. 11.16 Common theme: Turning on and off the signal Receptors are turned on (ligand binding) and off (ligand release) Second messengers can be turned on and off Enzymes can be turned on and off (by kinases and phosphatases)