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| Question | Answer |
| Multicellularity requires communication between cells; cells in multicellular organisms have a number of decisions to make: | - cell division- if they should divide - cell growth- how big - differentiation- make the decision to exit the cell cycle in order to undergo differentiation - movement- where and when - cell death- induced by intercellular signals |
| Signalling routes: Endocrine pathway | - A specialised endocrine cell secretes hormones into the bloodstream. Signalling factors inc hormones such as oestradiol, testosteron |
| Signalling routes: paracrine pathway | - signalling cell releases signalling factor which then diffuses into the extracellular matrix, reaching target cells in the vicinity. - limited by the distance over which the signalling factor can diffuse. |
| Signalling routes: Neuronal pathway | - neurons engage different type of signals; electrical ones in the form of action potentials and chemical ones in the form of neurotransmitters |
| Signalling routes: contact-dependent | - if the signalling route is membrane-bound |
| Examples of signalling factors | - hormones: signal via endocrine pathway in the bloodstream eg oestradiol, testosteron - growth factors: large class of protein factors secreted from cells eg epidermal growth factors - metabolic regulators: mediate immediate responses to changes in the enviroment eg insulin, glucagon, adrenaline - neurotransmitters, released by neurons in the CNS eg acetylcholine, glutamate, GABA - migratory cues- whether to move or not eg platelet derived growth factor |
| Signal transduction | - all signalling factors bind to specialised receptor molecules on the surface of target cells - each target cell 'understands' the specific receptor as it has a specific binding site for it. If this is not present it is said to not be 'competent' to respond to the signal. - most receptors are membrane bound, transmembrane proteins with an extracellular domain that binds to the signalling factor, and an intracellular domain that responds to binding, transducing signal into the cell. |
| 2 things that can happen intracellularly in response to binding | Either: 1. the reactions caused by the intracellular domain cause a cascade of altered protein functions, directly affecting cell machinery causing an immediate fast response. 2. where intracellular domain causes a cascade of intracellular signals, ultimately affecting gene transcription, resulting in a long-term change of cell activity. slow and long lasting. |
| Receptors | - can be turned off - most receptors are membrane bound factors (transmembrane) - bind ligands with high selectivity and affinity |
| Receptors: cell surface receptors | - in the plasma membrane of the surface of the cell - hydrophillic signal molecules diffuse through cytoplasm to bind cell surface receptors - conformation change is induced, which transduces signal from the outside of the cell to the inside. |
| Receptors: intracellular receptors | - typically bind small, hydrophibic signalling molecules eg hormones, that diffuse into the cell. - often act as transcription factors; bind in cytoplasm and move into nucleus. - intracellular receptors are dedicated to intracellular hormones and signalling factors |
| Major membrane receptor families | - ion channels: eg nicotinic ach receptors - G protein-coupled receptors eg adrenaline - enzymes- mostly protein kinases eg EGF receptor |
| Receptors: ion channels | - typically found in neuronal membranes - highly selective for different types of ion - open pore (due to binding of signal molecule) allows ions across the membrane, down their conc gradient eg sodium ion channel |
| Receptors: G protein-coupled receptors GPCRS | - G proteins are very large - all g-protein coupled receptors have the same overall structure - all GPCRs are multipath transmembrane proteins, cross membranes 7 times with their 7 alpha-helical transmembrane domains. - amino domain of the protein sticks out into the intra-cellular space - domain between 5th and 6th protein is typically larger, interacts with secondary signalling factors; G proteins |
| action of G-protein-coupled receptors | 1. signal binds to receptor 2. g-protein associates with receptor 3. GDP/GTP exchange 4. G protein disassociates into Ga-GTP and Gby subunits 5. Ga-GTP activates effector enzyme (adenylyl cyclase) 6. Effector enzyme produces secondary messanger (cAMP) 7. Ga subunit hydrolyses GTP to GDP, Gaby complex re-associates, signal ends |
| cAMP | - acts as a secondary messenger - activates protein kinase A (PKA) - Protein kinases consist of 2 subunits, one regulatory and one catalytic. When levels of cAMP increase, it binds to the regulatory subunit, which releases the catalytic subunit. - catalytic subunit can then phosphorylate a number of different target proteins, driven by ATP. - amino acids that are typically phosphorylated include serine, theronine and tyrosine. |
| Example of a G-protein coupled receptor pathway: reaction of cells to adrenaline; the 'fight or flight' hormone | 1. adrenaline binds to the g protein receptors; b-adrenergic receptors on muscle cells 2. this activates it, resulting in adenylcyclase being activated, and cAMP levels increasing in muscles 3. This results in increased activation of protein kinase A (PKA) 4. PKA then starts to phosphorylate a number of different target proteins; 2 of which are glycogen phosphorylase and glycogen synthase 6. By inhibiting glucose synthase PKA decreases glycogen synthesis 7 by stimulating glycogen phosphorylase PKA induces glycogen degregation -so overall level of glycogen in muscle cells increases, preparing muscles for activity |
| G-protein coupled receptor activation: Receptor activation of protein kinase C (PKC) | 1. signalling molecule binds to g-protein, which activates it through exchange of GDP/GTP on the alpha subunit 2. this activates phospholipase C 3. Phospholipase C hydrolyses inositol phospholipids, linked to sugar groups, breaking them down into lipid diglycerol and inositol 1,4,5 triphosphate. 4, these 2 molecules act as secondary molecules, triggering cascades: - Lipid dicylgerol activates PKC, which then goes onto activate a number of target proteins - IP3 also activates a number of target proteins, one of these being calcium ion channels on the ER, allowing calcium to move out of the ER, which then goes onto trigger more reactions. |
| Summary: the 2 different G-protein coupled receptor pathways | - B-adrenergic receptor, Gs protein coupled. Effector enzyme adenylyl cyclase which activates the secondary messanger cAMP AND - a1-adrenergic receptor, Gq protein coupled. Effector enzyme is phospholipase C which activates the secondary messanger DAG and IP3 which results in calcium efflux - Both of these pathways can be activated by adrenaline- |
| Receptor kinase pathway | - typically activated by growth factors, for example ECF 1. Growth factors bind to transmembrane protein kinases 2. this activates intracellular factors called RAS, which binds to to GDP 3. this triggers a cascade of protein kinase activation: Cascade: 1. activated RAS activates the protein kinase RAF 2. Which activates the PK MER1/2 3. which activates the PK ERK 1/2 4. this affects the factors that go into the nucleus and affect gene expression. Cascade amplifies the signal. |
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