cell signalling Flashcards
Define homeostasis
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 counteracts any deviations from the set point(e.g. when blood glucose level goes higher than set point, insulin is secreted to return glucose levels to set point).
Describe the features of 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)
Describe the 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* directly 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)
Describe the 3 stages of cell signalling
- ligand-receptor interaction
- signal transduction
- cellular response
- 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.
Note: Ligands are usually too large* to pass through any transient pores* of the cell surface membrane or are hydrophilic* and cannot pass through the hydrophobic core* of the cell surface membrane
- Signal transduction
→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 signalling proteins (e.g. kinases) or small molecules(e.g. cAMP)or ions.
→kinases** phosphorylate** and usually activate* proteins and are involved in multiple catalytic* steps in a signal transduction pathway. Hence kinases allows amplification* of the signal
→phosphatases* dephosphorylate* and usually inactivate* proteins and are involved in multiple catalytic* steps in a signal transduction pathway. By dephosphorylating and inactivating proteins, they can inhibit signal transduction.(Do note that phosphorylation can inactivate some proteins while dephosphorylation can activate some proteins)
Advantages of a cell signalling pathway
- 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* - One signal molecule can trigger multiple signal transduction pathways in a cell* and elicit many different cellular response*
- when blood glucose levels are high, insulin can bind to RTK and increase rate of glycolysis, glycogenesis, protein and lipid synthesis , etc - 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 can trigger signal transduction pathways in the cell)
- Ensures specific reactions* are triggered as a specific signal* will bind to a specific receptor* and will elicit specific reactions* in specific cell types*
- Provides many checkpoints for regulation* as cellular responses can be terminated/regulated at:
(i) AtReception:
→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.
- A signal molecule can activate genes* in nucleus* upon binding to cell surface receptor without the need to move into nucleus **
Describe the structure of the G-protein linked receptor
- G protein coupled receptor (GPCR) is cell surface receptor that will bind to specific signal molecule and initiates the process of signal transduction which converts the information in the signal from the outside of the cell into a cellular response within the cell.
- GPCRs consist of a single polypeptide* with an extracellular N-terminus, and an intracellular C-terminus.
- GPCR is a globular* seven pass transmembrane **protein with a tertiary structure*.
- GPCR consists of 7 α-helices connected by three intracellular and three extracellular peptide loops.
- As a transmembrane protein that is embedded in a cell’s plasma membrane, it is folded such that its amino acid residues with hydrophobic R groups* are interacting with the hydrophobic core* of the phospholipid bilayer *the plasma membrane and
- its amino acids with hydrophilic R groups* are arranged within the interior* of the protein and also interact with the aqueous interior* and exterior of the cell *as well as the hydrophilic phosphate heads of phospholipid bilayer**.
- The extracellular* loops have a ligand binding site** at which a specific* signalling molecule (e.g. glucagon) can bind to the GPCR.
- The intracellular domain* of GPCR has a G protein binding site** that allows binding of a heterotrimeric G protein complex.
- When a ligand binds to the ligand binding site at the extracellular side of a GPCR it causes a conformational change** of the intracellular domain** at the cytoplasmic side of the GPCR such that it can bind to an inactive G protein
- The bound G protein* is activated by exchanging its bound GDP for a GTP**.
Qn: Explain how the molecular structure of the epinephrine receptor show in Fig2.1 enables it to function as a G-protein linked receptor [4m]
structure: function
- The extracellular domain has a ligand binding site which is complementary** in shape and charge** to epinephrine to bind to it*
- The intracellular domain of epinephrine receptor has a binding site* which is complementary** in shape and charge to the G protein* ;
- to allow binding and activation of G protein
- The epinephrine receptor is a G protein linked receptor which has a transmembrane region with amino acid residues with hydrophobic R groups** that interact with the hydrophobic core* of the phospholipid bilayer
- to allow it to embed in the membrane
Outline how the insulin regulates the concentration of blood glucose
- An increase in blood sugar level above 90 mg/dL
- Is detected by the beta cells of islets of Langerhans of pancreas
- which secretes insulin
- which recognises and binds to cell surface receptors known as insulin receptors (RTK) which exists as linked dimers** on the liver (or muscle) cell/ or / when the specific ligand binds to complementary extracellular ligand-binding site of a specific receptor, causes dimerisation where 2 dimers assemble into a pair
- ligand-binding causes RTK to undergo changes in conformation** in its intracellular*, cytoplasmic domain
- the conformational change activates* tyrosine kinases* in each of the subunits of the receptor and triggers crossphosphorylation* of tyrosine residues ( where kinases on 1 subunit crossphosphorylates tyrosine residues on the other subunit)
- phosphorylated tyrosine residues serve as docking sites* for other relay proteins
- relay proteins activated by binding or via phosphorylation by RTK
- relay proteins may be kinases which can go on to phosphorylate other proteins when activated
- phosphorylation initiates the sequential activation of kinases resulting in a phosphorylation cascade which eventually activates glycogen synthase** which catalyses glycogen synthesis from glucose (i.e. increase glycogenesis* in liver and muscle cells)
other cellular responses:
- translocation of glucose transporters from the membrane of cytoplasmic vesicles to the cell surface membrane. this increases glucose intake into cells as it increases permeability of the cell to glucose
- increased rate of glycolysis
- increased lipid & protein synthesis
- blood glucose levels decreases
- -> detected by the receptor which then decreases insulin production
Outline how glucagon regulate the concentration of blood glucose
note: G protein has intrinsic GTPase activity** which can hydrolyse GTP to GDP and inactivate the G protein, terminating the cellular response
- A decrease in blood glucose level below 90mg/dL
- is detected by the alpha cells* of islets of Langerhans of pancreas
- which secretes glucagon*
- which recognises and binds to cell surface membrane known as GPCR
- on the liver* cell
- ligand-binding causes GPCR to undergo changes in conformation** in its intracellular* cytoplasmic domain**
- this conformational change causes an inactive G protein** to bind to the GPCR, and release its bound GDP and allow GTP to bind in its place
- GTP binding causes conformational change** in the G protein, activating it**
- Activated G protein dissociates from the receptor and translocates along the cytoplasmic side* of the cell membrane to bind to an active an enzyme, adenylyl cyclase**
- Adenylyl cyclase converts ATP to cAMP** (2nd messenger which activates Protein Kinase A**
- Activated protein kinase A can phosphorylate other proteins
- Protein Kinase A initiates the sequential activation of kinases resulting in a phosphorylation cascade which eventually activates glycogen phosphorylase** which catalyses the breakdown of glycogen to glucose* (i.e. glycogenolysis)
other cellular responses:
- increased gluconeogenesis**
- blood glucose levels increases
- this is detected by the receptor which then decreases glucagon production
Explain the role and nature of second messengers
- small, non-protein, water soluble molecules or ions
- can readily spread throughout the cell by diffusion and activate cellular proteins
- can participate in pathways initiated by both GPCR and RTK
(e. g. cAMP –> synthesised from ATP by adenylyl cyclase - -> activates protein kinase A which phosphorylate other proteins in a signal transduction pathway)
Qn: Why insulin receptors found outside of cells, never inside
- Insulin to large to pass through the transient pores of cell surface membrane
- insulin cannot pass through hydrophobic core of cell surface membrane because it has polar regions and will not be repelled
Describe how cAMP increases blood glucose concentration [3m]
- cAMP acts as a secondary messenger** in the glucagon signalling pathway
- numerous cAMPs which are small, non-protein, water soluble* molecules are able to diffuse quickly** throughout the cytosol to
- activate many other relay molecules** thus leading to the activation of other kinases involved in the break down of glycogen to produce large amounts of glucose** in liver cells
- the glucose molecules are then released into the bloodstream causing glucose concentration to increase
Main effects of insulin on target cells [6m]
- Binding of insulin to insulin receptor will lead to cellular response such as trigger the translocation of vesicles with glucose transporter-4 *****to the plasma membrane of the target cells
- this will increase the no of GLUT-4 receptors on the plasma membrane
- increasing the permeability** of the plasma membrane to the glucose increasing glucose uptake from the blood by cells, causing a fall in glucose concentration
- glucose taken up by the cell will be used to synthesise glycogen** via glycogenesis
- glycogen synthesis catalysed by glycogen synthase which is an enzyme activated as a result of insulin signalling
- glucose taken up by the cells will increase the rate of glycolysis and can also be broken down by aerobic respiration to form intermediates which is then used for fatty acid synthesis ***
Explain the roles of kinases (such as PhK)and phosphatases in cell signalling. [4]
- Kinasescatalyse the addition of phosphate* groups from ATP* to a protein;
- Kinases activate a large number of molecules resulting in signal amplification;
- Phosphatases catalyse theremoval of phosphate*groups fromproteins by hydrolysis.
- Phosphatases inactivate relay molecules so that propagation of the signal will be inhibited/signal will be terminated.
define signal amplification
each activated protein is able to activate many molecules involved in the next step of the pathway of a cascade reaction
