16) Homeostasis Cell Signaling Summary 9744 2019

Energy and Equilibrium (9744) Homeostasis & Cell Signalling 2019 Prepared by Mrs.S.Nair, Mrs.Wong SH & Mdm.S.Cross Raffles Institution 1 Homeostasis and Cell Signalling  Homeostasis refers to the maintenance of a stable internal environment independent of fluctuations in the external environment by self- regulating & negative feedback mechanisms so that the organism can function optimally. Self-regulation: where a corrective mechanism is triggered by the very entity which is to be regulated (e.g. control of blood glucose levels is triggered by changes in blood glucose levels) Negative feedback: a mechanism which brings about increasing stability of a system i.e. it removes any deviations from the set point i.e. a change in a variable triggers a response that counteracts the initial change. (e.g. when blood glucose level goes higher than set point, insulin is secreted to return glucose levels to set point).  Hormones:  secreted by endocrine glands (ductless glands) directly into the bloodstream  effective in small quantities (as signal amplification, that occurs during signal transduction, will lead to the production of a strong cellular response)  act on specific target cells which have specific cell surface receptors  each type elicits different cellular responses & after having served their function, are rapidly broken down  e.g. insulin & glucagon are hydrophilic peptide hormones that bind to the specific receptors on the cell membrane (e.g. RTK & GPCR)  Pancreas:  is an organ that is both an endocrine (islets of Langerhans) gland & an exocrine (acinar cells) gland  the islets of Langerhans contain alpha cells which secrete glucagon and beta cells which secrete insulin into the bloodstream (insulin and glucagon (which are protein in nature) are secreted constantly and work in an antagonistic fashion; it is their relative concentrations and not their actual levels that are critical to maintain normal blood glucose levels at the set point which is 90mg/dL)  Glucose:  key respiratory substrate  Glycogen:  stored in liver and muscles  Insulin triggers the conversion of glucose to glycogen  Glucagon triggers the conversion of glycogen to glucose (It is incorrect to say that insulin converts glucose to glycogen as insulin binds to the insulin receptor which triggers a si gnal transduction pathway that eventually leads to the conversion of glucose to glycogen in the cell. Likewise, it is incorrect to say that glucagon converts glycogen to glucose.)  A deviation from the set point i.e. stimulus (e.g. high blood glucose levels)  is detected by detectors (e.g. beta cells in islets of Langerhans) (N.B. Sometimes detectors are referred to as receptors)  which secretes an appropriate signal (e.g. insulin)  which binds to the cell surface receptors** of the cell (e.g. cell surface insulin receptor, RTK) of the effector (e.g. liver/muscle cells)  which brings about an appropriate response that restores the condition to the set point (e.g. blood sugar levels return to set point)  this serves as negative feedback to detectors (e.g. beta cells) to decrease secretion of signal (e.g. insulin)  Cell signaling (3 stages) and role of kinases and phosphatases in signal amplification: 1) Ligand-receptor interaction:  ligand/signal/first messenger binds to a specific, ligand-binding site (which is complementary in shape and charge to the ligand) on the extracellular domain of the cell-surface receptor to form a ligand-receptor complex. 2) Signal transduction & amplification:  where binding of the ligand/signal to the protein receptor causes a conformational change in the intracellular domain of the protein receptor which initiates the signal transduction. i.e. the signal is converted to a form that can bring about a specific cellular response.  signal transduction usually occurs in a series of multiple catalytic steps in a signal transduction pathway  the multiple catalytic steps allow amplification of the signal, where the number of activated molecules increases with each subsequent step.(Hence signal amplification occurs during signal transduction.)  the signal transduction pathway is mediated by intracellular signaling proteins (e.g. kinases) or small molecules (e.g. cAMP) or ions.  kinases phosphorylate and activate proteins and are involved in multiple catalytic steps in a signal transduction pathway. Hence kinases allows amplification of the signal  phosphatases dephosphorylate and inactivate proteins and are involved in multiple catalytic steps in a signal transduction pathway. By dephosphorylating and inactivating proteins, they can inhibit signal transduction. 3) Cellular response:  where the t ransduced signal triggers specific changes in cellular function, me tabolism, or development by changing gene expression by targeting proteins such as gene regulatory proteins, ion channels, components of a metabolic pathway etc. * Advantages of a cell signaling pathway: 1) Facilitates amplification of signal  small number of signal molecules binding to the receptors can produce a large cellular response as the number of activated molecules increases with each catalytic step in the pathway 2) One signal molecule can trigger many signal transduction pathways in a cell and elicit many different cellular responses  when blood glucose levels are high, insulin can bind to the RTK and increase rate of glycolysis, glycogenesis, protein and lipid synthesis etc.) 3) Provides many checkpoints for regulation as cellular responses can be terminated/regulated at (i) At Reception:  extracellular first messenger can be degraded by enzymes in the extracellular space  endocytosis of cell surface receptors to prevent ligand-receptor interaction can prevent signal transduction  endocytosis of the entire ligand-receptor complex can prevent signal transduction (ii) During Signal Transduction Pathway  production of phosphatases dephosphorylate & inactive the relay proteins  inhibit further signal transduction  production of inhibitors that bind to the intracellular domain of the ligand-receptor complex and /or any of the intracellular signal proteins in the signal transduction pathway to prevent transduction of the signal. 4) One type of signal can allow the coordinated activation of many different cells simultaneously (e.g. insulin can bind to receptors on liver and muscle cells and trigger signal transduction pathways in the cell.) 5) Ensures specific reactions are triggered as a specific signal will bind to a specific receptor and will elicit specific reactions in specific cell types. 6) A signal molecule can activate genes in nucleus upon binding to cell surface receptor without the need to move into nucleus.

Energy and Equilibrium (9744) Homeostasis & Cell Signalling 2019 Prepared by Mrs.S.Nair, Mrs.Wong SH & Mdm.S.Cross Raffles Institution 2 Outline how insulin and glucagon regulate the concentration of blood glucose through the respective tyrosine kinase receptor and G- protein linked receptor INSULIN GLUCAGON A stimulus An increase in blood sugar level above 90 mg/dL A decrease in blood sugar level below 90 mg/dL    is detected by a detector/receptor (which is a cell that detects the change) is detected by the beta cells of islets of Langerhans of pancreas is detected by the alpha cells of islets of Langerhans of pancreas    which releases a ligand/signal (e.g. insulin/glucagon) which secretes insulin (1st messenge