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Cell signalling
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- 1Characteristics of hormone receptorsHigh affinity for hormone
Hormone specific
Binding is saturable - response range - 2Receptor classesLigand-gated channels (nicotinic)
G protein coupled (muscarinic)
Enzyme-linked (insulin receptor)
Intracellular receptors (vit D receptor) - 3Direct control of an ion channel: nicotinic ACh receptor at the NMJLigand binds to the site on the receptor causing either depolarisation or hyperpolarisation in a timescale of milliseconds - fast response but effect doesn't last long
- 4Cobra venom neurotoxinCauses acetylcholine nicotinic receptor to jam open so all membranes become hyperpolarised leading to respiratory failure
- 5Direct control of an ion channel: the KATP channel complexThe channel is open at rest and when you eat, ATP is taken up which binds and shuts the channel allowing insulin secretion
In this way, glucose is coupled with insulin release - 6G-protein coupled receptor superfamily (791 genes)Class A: endogenous ligand/orphan; offactory/pheromone (661 genes)
Class B: secretin (15 genes)
Class C: glutamate (22 genes)
Others: adhesion, frizzled, taste receptors (92 genes)
Most are in the rhodopsin family of the class A receptors (761). These all look very similar meaning it is very difficult to produce very specific drugs - 7Structure of G-protein coupled receptors7 transmembrane domains with glycosylated and phosphorylated regions
- 8The heart M2 muscarinic receptor with bound agonist QNBSlows heart rate
- 9G-proteinsGet their name from their ability to bind GTP (active) and GDP (inactive)
Active G proteins bind and activate 'signalling' enzymes causing a specific response - 10The G protein is heterotrimericIt has alpha, beta and gamma subunits which are not usually associated with a receptor in the GDP form. The alpha is the major subunit
- 11MechanismThe hormone binds to the receptor, which activated the G-protein resulting in the activation of an enzyme which mobilises a second messenger and causes a cell function
- 12G-proteins are involved in the responses to the majority of hormonesProtein hormones e.g. glucagon
Amines e.g. adrenaline
Lipids e.g. prostaglandins - 13The G-protein is heterotrimeric and contains 30-40 genesGq - activates phospholipase C (PLC)
Gi - inhibits adenylate cyclase (AC) activity and therefore the production of cAMP from ATP
Gs - stimulates adenylate cyclase activity causing the formation of cAMP
G12-13 - Rho family
Gbeta - activates inwardly-rectifying potassium channels - 14Downstream effectorsAdenylate cyclase (AC)
Phospholipase C (PLC)
Ion channels
These all result in signal amplification - 15G-protein control of adenylate cyclaseGs: hormones binding to the receptor stimulates AC which converts ATP to cyclic AMP, which is degraded into protein kinase A and 5' AMP by phosphodiesterase which splits the catalytic and regulatory regions
Gi: inhibits adenylate cyclase by not converting ATP into cyclic AMP - 16Cholera toxinBinds to the GM1 receptor which stimulates the Gs protein, resulting in the conversion of ATP into cAMP by adenylate cyclase
cAMP causes the insertion of an increased number of CFRTs into the membrane of the epithelial cells of the gut
The massive upregulation of CFTR allows for more Cl- to leave the cell, resulting in the loss of Na+ and hence the loss of water - die from dehydration - 17Adrenal cortex produces steroid hormones under Gs controlACTH (adrenocorticotrophic hormone) from the anterior pituitary gland
- 18cAMP in adrenal cortex cells stimulates steroid hormone synthesis by activating protein kinase AWithin minutes a cholesterol ester hydrolase converts a cholesterol ester into cholesterol which is moved into the mitochondria
Within hours, there is transcriptional upregulation - 19G-protein activation of phospholipase CHormone bound to the receptor causes the activation of phospholipase C, which in turn catalyses the cleavage of PIP2 (phosphatidylinositol bisphosphate). This then activates DAG (diacylglycerol), which stimulates protein kinase C resulting in protein phosphorylation and activation. PIP2 also stimulates IP3 (inositol triphosphate) causing the release of Ca2+ from the endoplasmic reticulum, which binds to calmodulin and causes the activation of intracellular proteins
- 20G proteins can also activate ion channels e.g. with the muscarinic M2 receptor in the heartThis is done through the activation of the G protein resulting in the opening of the K+ ion channel causing depolarisation, and hence slowing the heart rate
The ryanodine receptor is another example of a G-protein activated ion channel which results in the contraction of smooth muscle - 21Reaction cascades cause massive amplificationOne receptor can activate multiple G-proteins, which can then activate a multitude of ion channels or enzymes (PLC or PKA) causing a host of second messenger molecules (cAMP, DAG and IP3) to activate protein kinases and phosphatases
The target proteins are often transcription factors and enzymes
The response is often large and maintained lasting days, weeks, and in the case of fatty acid phosphorylation, months - 22GPCR neurotransmittersNoradrenaline
Glutamate
Dopamine - 23Enzyme-linked receptors - the receptor is also the effector enzymeTyrosine kinase or guanylate cyclase enzyme activity in intracellular face of receptor
- 24Receptor dimerise upon ligand binding causing protein phosphorylation which results in a cell functionTimescale: minutes
E.g. insulin, EGF receptors - 25Insulin receptorsInsulin binding causes tyrosine kinase activation which results in the autophosphorylation of the receptor causing the movement of Glut4 into the plasma membrane. This pumps glucose into the cell, so glucose can be absorbed
This is seen in skeletal muscle and the liver - 26Intracellular receptors: control of DNA transcription - steroid hormines/vit D for the absorption of Ca2+ into the gutThe passive diffusion of a steroid hormone into the cytoplasm of a cell binds to a steroid receptor. This diffuses into the nucleus, where it controls gene transcription resulting in protein synthesis
This is the slowest response (hours) as passive diffusion is very slow - 27Steroid receptor structureN terminus-C terminus
Transcriptional regulation region
DNA binding region
Hormone binding region
DNA strand contains specific hormone response elements - 28Intracellular receptors: Reproduction: Androgens Estrogen ProgesteroneAdrenal:
Glucocorticoids
Mineralocorticoids
Thyroid:
Thyroid hormone
Ca2+
Vitamin D - 29Turing off the signalRemoval or degradation of the hormone
Desensitisation of the receptor
Internalisation of the receptor - 30Desensitisation of G protein receptorsGRK (G-protein receptor kinase) phosphorylates the N-terminus of the G-protein causing arrestin to bind to the protein, preventing GTP binding
- 31ResensitisationIntegration: PDE (phosphodiesterases) serves as the connection between two different pathways - insulin and glucagon
PDEs inhibit cAMP by breaking it down in the cell - 32Receptor internalisationPrevents brain from over-stimulation
Amphetamines stimulate internalisation
Long-term abuse stimulates transcription factors to silence the genes encoding the receptors (i.e. stops dopamine receptor expression)
Once transcription has been silenced, it is not possible to reverse this - 33Receptors and diseasesFailure of ligand binding
Failure of signal transduction
Constitutively active receptor systems
Antibodies to receptor (motor neuron disease) - 34Receptor mutationsInactivating - receptor does not function despite the hormone being present
Activating - receptor continually active without hormone bound - 35GHRH (growth hormone releasing hormone) - inactivating receptor mutations - pituitary dwarfisnThe hypothalamus releases GHRH
The GHRH receptors normally cause the release of GH which causes long bone and muscle growth, however the receptors are blocked
Because we can sequence the gene for the defective channel, synthetic HGH made in yeast can be administered - 36Activating receptor mutations - precocious pubertyThe anterior pituitary gland releases LH which binds to LH receptors in the ovary and testes. cAMP is activated and then causes the production of oestrogen and testosterone. The LH receptors are permanently switched on and puberty occurs early
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- Cells Karteikarten am Cell signalling, erstellt von Eleanor Smith am 20/01/2019.
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