cell communication Flashcards

Question

what happens when you have too little cortisol (disease)? include the distinction between primary and secondary forms of the disease

Answer 1

Addison’s disease, primary version is due to autoimmune response damaging adrenal glands, secondary version is due to a lack of ACTH (give someone ACTH to differentiate between the two) If your body experiences stress (an accident, an operation, an infection etc…) and it cannot respond, addisonian crisis occurs, super low blood sugar and some other severe symptoms, body shuts down

Answer 2

too much cortisol often caused by tumour of pituitary gland = too much ACTH = too much cortisol (also known as dexamethasone) Also caused by long term steroid abuse, can cause raised blood pressure and weight gain and puffy face, you stop responding to own cortisol so issues occur if athletes who take cortisol decide to stop

Answer 3

(too much insulin) brain can only metabolise glucose - so super low blood sugar is very dangerous

Answer 4

high blood sugar over prolonged periods (hyperglycaemia) due to destruction of beta cells in islets of Langerhans often following viral infection that causes an autoimmune response = no insulin being produced glucose in blood not taken up = effecting osmotic potential glucagon depletion - Without the inhibitory effects of insulin, the alpha cells in the pancreas release more glucagon. This excess glucagon, exacerbates hyperglycemia can cause polyuria and hypertension risk increases as BMI increases

Answer 5

low insulin production but mainly peripheral insulin resistance (desensitised receptors) which can be linked to obesity treatment - Some treated with insulin/insulin stimulating drugs as its levels are lowered, but also drugs to improve efficacy of the resistant receptors known as biguanide drugs not curable but can be prediabetic and take measures to reduce obesity and ‘turn it around’ symptoms - Increased thirst, hunger, urination, fatigue and blurred vision

Answer 6

Type II diabetes patients One group had typical care Other group had rigorous exercise and diet to manage weight, no medicines Results showed the second group lost more weight than the other group and had more people who reversed their diabetes (40% after 12 months, a bit less after 24 months) Mostly white people tho (some evidence suggest diabetes in south asian people is less linked to BMI)

Answer 7

insulin signalling is conserved in animals flies with restricted insulin signalling actually lived longer, possibly due to caloric constriction - for them, eating less extended life

Answer 8

Metformin inhibits mitochondrial complex I, preventing the production of mitochondrial ATP leading to increased cytoplasmic ADP : ATP and AMP : ATP ratios These changes activate AMP-activated protein kinase (AMPK), an enzyme that plays an important role in the regulation of glucose metabolism

Answer 9

The receptor is a heterotetramer - it has four subunits, two alpha ones and two beta ones They are linked by disulphide bonds The alpha ones are extracellular and have a ligand binding site The beta ones are transmembrane subunits, with their ends in the cytoplasm exhibiting tyrosine kinase activity

Answer 10

Receptor activation initiates a cascade of phosphorylation events that leads to the activation of enzymes which control many aspects of metabolism and growth 1. Ligand binds causing a conformational change, dimerisation 2. Kinase domains 'trans-phosphorylate’ 3. At the same time, an associated docking protein known as ‘ISR 1’ (insulin receptor substrate 1) also gets phosphorylated at a tyrosine residue 4. Once phosphorylated, IRS binds to lipid kinase PI3K, which synthesises PIP3 at the plasma membrane 5. PIP3 recruits PDK (another kinase) which phosphorylates AKT 6. AKT then phosphorylates lots of things at both Ser and Thr residues, including transcription factors and glycogen synthase kinase Long story short, when activated it causes a cascade of many phosphorylations

Answer 11

Hydrophilic extracellular domain to interact with the ligand Most will have ‘conserved’ elements that are immunoglobulin like Transmembrane domain - 20-25 Aa of alpha helical structure, hydrophobic, stabilised by lipid bilayer fatty acid chains Has to be trafficked to the membrane - this is done by signal-peptides Intracellular domain - hydrophilic, has tyrosine kinase activity to interact with downstream machinery

Answer 12

Dimerisation of single-pass transmembrane domains (pulls extracellular domains of two receptors together so they can do something e.g. phosphorylate one another) Tyrosine kinase receptors have enzymatic activity themselves, often phosphorylating each other upon dimerisation (working in ‘trans’), resulting in a phosphorylation cascade of some kind

Answer 13

ligand binding = dimerisation = trans phosphorylation from here it goes Ras/Raf/MEK/ERK The sites on the receptor that get phosphorylated are used as docking domains for SH2 domains (a domain present in many proteins for the purpose of binding to RTKs) In this case the SH2 domain of the ‘adaptor protein’ Grb2 Grb2 then ‘grabs’ Sos - a GTP to GDP exchange factor - GEF Sos can then swap GDP to GTP in the membrane associated Ras molecule - activating it This membrane -tethered Ras has GTPase activity This means it naturally would switch itself off by getting the GTP back to GDP This will only be possible when Sos is no longer around The active Ras-GTP binds to Raf This results in loss of Raf’s inhibitory domain and Raf is now active Raf phosphorylates itself (this is now Ser/Thr phosphorylation) Raf phosphorylates MEK, which does the same to ERK - this goes into the nucleus to activate transcription factors

Answer 14

Raf is regulated at many points in this pathway 1. Raf is regulated by its own N-terminal region 2. Also regulated by the 14-3-3 protein 3. Erk - the final kinase - also is involved in negative regulation and can phosphorylate Sos to prevent it being ‘grabbed’ by Grb2

Answer 15

In the Ras/Raf pathway, issues can lead to cutaneous melanomas Inhibitors of B-RAF’s kinase activity have been developed to treat malignant melanoma Very effective at first but even if tiny percentage of mutated B-RAF kinases aren’t inhibited those cells survive and grow So if extracellular signalling is fine, it still means intracellular signalling is over-working B-RAF and MEK (further downstream) are both targeted with inhibitors as its very unlikely that there cells with resistant forms of both these proteins

Answer 16

B-RAF and MEK (further downstream) are both targeted with inhibitors as its very unlikely that there are cells with resistant forms of both these proteins

Answer 17

So there's a cytokine receptor on a T cell - which is a single pass transmembrane receptor These receptors bind to cytokines or MHC molecules - molecules on cells that have bound to and are presenting antigens to the T cells The receptor is associated with this is JAK, which is a tyrosine kinase (Don't have the tyrosine kinase built in, use JAK, an associated tyrosine kinase) Binding of ligand = dimerization and transphosphorylation

Answer 18

The phosphorylation allows SH2 domains of STAT to bind STAT is phosphorylated, goes to the nucleus, binds DNA and results in transcription transcription of genes involved in cell proliferation for example

Answer 19

there's only 4 JAKs (kinases) and 7 STATs the pathway can be activated by different ligands, and have different downstream effects (so the pathway/molecules in the pathway are very versatile)

Answer 20

In JAK - Pseudokinase domain negatively regulates the kinase site JAK 2 works at 1% max capacity if uninhibited For disease to be reached it only needs to be 8%

Answer 21

myeloproliferative neoplasms - can cause production of too many 1. red blood cells - polycythaemia vera 2. platelets - essential thrombocythemia or too few red blood cells due to scaring - 3. myelofibrosis