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Cell Signalling
Organisation of the Body
| Question | Answer |
|---|---|
| Characteristics of hormone receptors | High affinity for hormone Hormone specific Binding is saturatable |
| Kds | Binding constant 10^-12 to 10^-9 Very little hormone needed for activation |
| EC50 | Conc of hormone that gives 50% response |
| Receptor classes | Ligand gated ion channels G protein coupled receptors Enzyme linked Intracellular receptors |
| Ligand gated ion channels | Open in response to NTs Leads to a change in membrane potential due to ion movement Instantaneous response |
| nACRs | 5 protein 2 homodimers and 1 extra protein Blocked by cobra toxins Open in response to ACh binding - non-selective cation channel |
| Katp channel | Glucose enters beta cells and is metabolised to produce ATP This binds to K channels and blocks them Leads to depolarisation and Ca influx Insulin release triggered ATP acts as a hormone |
| G protein coupled receptors | Hormone binds to receptor leading to G protein mobilisation They interact with enzymes through a second messenger system Timescale - seconds/minutes |
| What activates GPCRs | Protein hormones - glucagon Amines - adrenaline Lipids - prostaglandins |
| Family of GPCRs | Around 820 in the human body All have similar structures - hard to design drugs specific to one, so unwanted effects are common |
| Structure of GPCRs | 7 transmembrane regions Extracellular N-terminus Often post translationally glycosylated and phosphorylated to regulate activity |
| M2 muscarinic receptors | Found in the heart - slow heart rate QNB - antagonist |
| G proteins | Get their name from their ability to bind GTP and GDP They exist in an active GTP bound and an inactive GDP bound form Active G proteins bind and activate signalling enzymes causing a specific response Heterotrimeric - alpha, beta and gamma subunits |
| Types of GPCRs | Gq - activates PLC Gi - inhibits adenylate cyclase Gs - stimulates adenylate cyclase G12/13 - Rho family Gb - activates inwardly rectifying potassium channels |
| The G protein cycle | Inactive - loosly associated with proteins Ligand binds and recruits G proteins GTP exchange causes dissociation of the protein Subunits have different effects GTP hydrolysis causes reassociation |
| Downstream effectors of GPCRs | Adenylate cyclase Phospholipase C Ion channels |
| Adenylate cyclase | Stimulated by Gs and inhibited by Gi Converts ATP into cAMP This activates PKA by releasing its catalytic subunits cAMP degraded by phosphodiesterase |
| Effects of Cholera | A GPCR agonist Binds to Gs - increased cAMP and PKA Activates CTFR Overactive CTFR causes Cl loss into lumen of gut followed by Na and water Leads to internal dehydration Enkephalin - stimulates Gi to reduce effects |
| cAMP in steroid synthesis | ACTH stimulates Gs - cAMP produced Immediately upregulated cholesterol synthesis by cholesterol ester hydrolase Over a few hours allows uptake of cholesterol by mitochondria |
| PLC | Activated by Gq receptors Cleaves PIP2 into DAG and IP3 DAG activates PKC - phosphorylates proteins IP3 activates store operated calcium ion channels leading to Ca efflux from SR - activation of intracellular proteins |
| Role of Gq/Gs switch in beta cells | Normal B cells us a Gs pathway to secrete insulin involving GIP and GLP-1 Following chronic hyperglycemia and chronic sulfonylurea treatment they switch to Gq |
| Ion channels in GPCR | Channels phosphorylated - less active e.g. G protein gated inwardly rectifying potassium channels in the heart |
| Smooth muscle contraction | Uses multiple mechanisms Ligand gated ion channels Voltage gated ion channels Gq proteins - IP3 activates Ryr channels |
| Amplification | Reaction cascades cause massive signal amplification Proteins made can last a long time, so short activation affects function for longer periods |
| Enzyme linked channels | Receptor is also the effector enzyme e.g. tyrosine cyclase enzyme activity Receptors dimerise on ligand binding Autophosphorylation at tyrosine and serine residues |
| Insulin receptor | Tyrosine kinase receptor Leads to insertion of Glut4 into cell membranes Under fasting conditions no insulin = no glucose uptake as no Glut4 channels in membrane |
| Intracellular receptors | Control of DNA transcription e.g. steroid hormones and Vit D (for Ca uptake) Takes hours for proteins to be produced |
| Steroid receptor structure | DNA strand contains specific hormone response elements Contains regions for transcriptional regulation, DNA binding and hormone binding |
| What binds to intracellular receptors | Androgens Estrogen Progesterone Glucocorticoids Mineralocorticoids Thyroid hormone Vit D |
| Turning off the signal | Removal or degradation of the hormone Desensitisation of the receptor Internalisation of the receptor |
| Desensitisation of GPCRs | Phosphorylation of certain residues at the C terminus by GRK Arrestin binds to the receptor and prevents G protein interaction |
| Resensitisation | Phosphatases remove the phosphate from the C terminus Causes arrestin to dissociate |
| Role of phosphodiesterase's in glucose control | Serves as a connection between glucagon and insulin pathways Insulin drives activation of phosphodiesterase to downregulate the role of glucagon Breaks down cAMP |
| Receptor internalisation | Receptors taken into the cell by endocytosis Basically receptor mediated endocytosis Dopamine D1 receptors are permanently downregulated due to overuse in addiction - via internalisation and DNA metylation |
| What causes disease at receptors | Failure of ligand binding Failure of signal transduction Constitutively active signal receptor systems Antibodies to receptor |
| Inactivating receptor mutations | Receptor does not function despite hormone present |
| Activating receptor mutations | Receptor continually active without hormone bound |
| Dwarfism | Due to growth hormone releasing hormone inactivating receptor mutations No signalling - reduced growth hormone release No long bone or muscle growth Treated by administering growth hormone |
| Activating receptor mutations | Precocious puberty - puberty starting at 5-9 years Constant activation of LH receptors without the presence of the hormone Ovary - estrogen Testes - testosterone |
| Physiological response to receptor activation | Vesicle fusion Gene transcription Protein production |
| Types of cell signalling | Depolarisation induced - Ca entry dependant Depolarisation independent - Ca entry dependant |
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