membranes and receptors

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membranes and receptors
2010-12-27 12:53:08
membranes receptors

semester 2
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  1. main features of biological membrane structure
    40% lipids (phospholipid, cholesterol, glycolipid)
  2. what is a phospholipid?
    • general structure = glycerol backbone, 2x FA(C16/18), phyosphate group and head group (cholines,amines, amino acids, sugars...)
    • eg. phosphatidylcholine

    exception = spingomyelin - non glycerol backbone
  3. describe the structure of cholesterol
    • polar head group
    • 4 rigid planar steroid rings
    • non polar hydrocarbon tail
  4. what is a glycolipid?
    • replace phospho-headgroup with a sugar
    • cerebrosides - monomer
    • gangliosides - digosaccharides
  5. what are the properties of amphipathic molecules?
    contains both hydrophillic and hydrophobic moieties
  6. describe the process of formation of lipid bilayers
    VDW attraction of hydrophobic tails stabilised by non-covalent, electrostatic and hydrogen bonds


    hydrophillic moieties interact with water
  7. what is the difference between peripheral and integral proteins?
    peripheral held by electrostatic and hydrogen bonds - washed off by pHand ionic solutions

    integral within the membrane held by non polar interactions washed off by detergents/organic solutions
  8. what is the point of membrane assymetry?
    • allows proteins to carry out their function
    • the internal and external surface are different maintaining different external and internal environments
  9. describe the fluid membrane model
    • membranes are fluid structures:
    • lipid molecules can move in four ways flexion, fast axial rotation, fast lateral diffusion, flipflop.
  10. what is membrane fluidity?
    unsaturated bonds (double cis bonds) disrupt packaging of phospholipids increasing fluidity of the membrane
  11. what is cholesterols role in the membrane?
    • increase stability and increase fluidity
    • abolishes the endothermic phase transition of phospholipid bilayers - bonds by Hydrogen bonds to the beta-OH group on the FA so the polar ring structure reduces the mobility of the upper part of the FA tail stabilising the structure but also decreasing packing and thus increasing fluidity
  12. how can proteins move?
    what stops proteins moving?
    • conformational change
    • rotation
    • laterally

    restricted by: tethering, aggregation, interaction with other cells, the lipid mediated affect (preference for lower cholesterol)
  13. describe the cytoskeleton and its purpose
    • restricts lateral movement of membrane proteins and in RBCs allows for the necessary deformation to fit through small capillaries
    • network of spectrin and actin
  14. what are haemolytic anaemias?
    problems with erythrocyte skeleton > reduced RBC lifespan and bone marrow incapable of compensating

    • hereditary spherocytosis - spectrin levels depleted by 40-50%
    • hereditary eliptocytosis - spectrin can't for m hetromeres
  15. how do cells resist swelling?
  16. how do cells resist shrinkage?
  17. what are the properties of solutes that affect their movement through membranes?
    • hydrophobic - will go - eg: O2, CO2, N2, benzene
    • small uncharged polar molecules - will go - eg: urea, water, glycerol
    • large uncharged polar molecules - wont go - eg: glucose, sucrose
    • ions - wont go
  18. what are the differences between passive diffusion, facilitated diffusion and active transport?
    • passive: permeability and conc gradient
    • facilitated: uses ion channels/ gated pores
    • active: against conc/electrical gradient, uses energy
  19. how are ion concentrations regulated?
    • Na/K ATPase - K in Na out
    • Ca ATPase - (SERCA) - Ca into SR H out
    • Na/Ca exchanger - (NCX) - Na in Ca out
  20. what are the ion concentrations intra and extracellularly?
    OUTSIDE: K=4mM, Na=145mM, Cl=123mM, Ca=1.5mM

    INSIDE: K=155mM, Na=12mM, Cl=4.2mM, Ca=0.0001mM
  21. what is secondary active transport?
    symports and antiports using the Na gradient to move sugars, amino acids, ions

    • symports - same direction - Na/glucose transporter
    • antiports - opposite directions - NCX
  22. how is the pH of cytoplasm regulated?
    • sodium/pottasium ATPase creates a gradient for the NHE (sodium hydrogen exchanger - antiport Na in H out) - acidification opposed
    • anion exchanger - (Cl in HCO3 out) - bohr effect - alkalinisation opposed
  23. how is cell volume regulated?
    resist shrinkage/swelling
  24. describe the ionic basis of membrane potential
    • at rest K ion channels are open > k ions flow out down gradient
    • as anions cant follow the cell becomes negative inside compared to outside
    • equilibrium is reached when the membrane potential opposes the outward movement of K ions
  25. what is depolarization?
    • a decrease in membrane potential , so the inside becomes less negative
    • open sodium and calcium ion channels
  26. what is hyperpolarisation?
    • an increase in membrane potential
    • the inside becomes even more negative
    • open pottasium and chloride ion channels
  27. what is membrane potential?
    how is it measured?
    what is the normal value?
    • the electrical potential difference across the plasma membrane
    • measured by a fine micropippette (a microelectrode) filled with KCl which penetrates the membrane
    • expected values depend on cell type - skeletal muscle=-90mV, smooth muscle=-50mV, nerve cells=-50 to -75mV
  28. what is selective permeability?
    conformational change of gated membrane proteins - ion channels allows them to be open/closed and thus selective
  29. what is equilibrium potential?
    how is it calculated?
    equilibrium potential for an ion = the membrane potential at which there is no more net movement as diffusion is opposed by electrical forces.

    nerst equation = 61/z log ([ion]outside/[ion]inside)
  30. how do changes in ion channel activity cause changes in membrane potential?
    • channels are opened in two main ways: ligand gating and voltage gating
    • opening/closing changes permeability and thus membrane potential
  31. what are the roles of membrane potential in signalling?
    action potentials in nerves and muscles trigger and control muscle contractions and control secretion of hormones and neurotransmitters
  32. what is a synaptic potential?
    eg between nerve and muscle, nerve and nerve, nerve and gland
  33. what is the difference between fast and slow synaptic transmission?
    fast - the receptor is also a ligand gated ion channel, depolarising transmitters such as ACh and glutamate open channel to let in sodium, calcium and cations causing excitation of the cells the change they cause is called EPSP (excitatory postsynaptic potential).

    slow - the receptor is not itself an ion channel but signals to the ion channel via a G protein either within the membrane or through intracellular messengers
  34. what do hyperpolarising transmitters do?
    • eg. GABA and glycine
    • open channels to let in/out K or Cl they lead to inhibition the change they cause in the membrane potential is called IPSP - inhibitory postsynaptic potential
  35. what are the properties of action potential and its ionic basis?
    • action potential = a change in voltage across the membrane
    • only occurs if threshold is reached - all or nothing
    • they are propagated without loss of amplitude

    Na channels open then Na channels close and K channels open
  36. what is refractiveness?
    • after an action potential most of the sodium channels have been inactivated by maintained depolarisation the absolute refractive period is where nearly all the sodium channels are inactivated and during the RRP the sodium channels are recovering during this period it is more difficult to fire an action potential
    • this is the reason action potential only travels in one direction
  37. what is accommodation?
    the longer a stimulus last the larger the depolarisation necessary to initiate an action potential > the threshold becomes more positive > Na channel excitability is limited - hence why we use Ca in the heart
  38. what are the molecular properties of ion channels?
    • large membrane spanning proteins with an aqueous pore
    • which can be opened or closed by conformational change
    • sodium and calcium have 1 subunit
    • potassium has 4 subunits
  39. how do local anaesthetics work?
    • procaine/ligacaine
    • block the sodium channels
    • they are weak bases and cross the membrane in an unionised form
    • they work best when the channel is open and have a higher affinity for inactivated channels

    drugs could also stop action potential by blocking neurotransmitter release or binding to the anions involved
  40. how is conduction velocity measured?
    distance between anode and cathode / time
  41. how are axons raised to threshold?
    action potential is initiated by depolarisation to -55mV -threshold
  42. describe the local circuit theory of propagation
    • depolarisation of a small region of a neurones plasma membrane produces transmembrane currents in neighbouring regions depolarising them
    • as the sodium channels are voltage gated this causes more of them to open propagating the action potential
  43. what is the relationship between conduction velocity and fibre diameter?
    • in myelinated neurones conductance velocity is proportional to diameter - max velocity =120m/s
    • in unmyelinated neurones conductance velocity is proportional to the square root of diameter - max velocity = 20m/s
  44. what is myelination?
    • cells begin to be myelinated about 4 months after fertillisation
    • myelin reduces capacitance and increases the resistance of the axon
    • peripheral axons are myelinated by schwann cells
    • in the CNS oligodendricytes myelinate axons
    • in myelinated axons saltatory conduction occurs
    • myelination allows for increased conduction without incresed diameter
  45. what is saltatory conduction?
    • sodium channels are grouped at the unmyelinated nodes of ranvier
    • because the cytoplasm is electrically conductive and the myelin prevents the leak of charge depolarisation at one node of ranvier is sufficient to raise the next node to threshold and trigger an action potential
    • this reduces energy expenditure and increases speed
    • internodal distance is about 1mm
  46. what is demyelination?
    • caused by diseases
    • CNS- multiple sclerosis (all), devic's disease (optic and spinal cord)
    • PNS - laundry-guillian-barre syndrome, charcot-marrie-tooth disease

    autoimmune attack of schwann cells

    • partial demyelination - permanent failure
    • complete demyelination - slow motor skills as nerve gradually becomes an unmyelinated nerve

    could potentially treat with a k channel blocker as they lengthen action potential increasing the chances of propagation
  47. how do action potentials open calcium channels in the cell membrane?
    • at the nerve terminal depolarisation opens voltage gated calcium channels
    • calcium enters the cell raising its intracellular calcium concentration and this causes the cell release neurotransmitter by exocytosis
  48. name some types of calcium channels where they are found and what blocks them
    • L - neurones, muscles, lungs - DHP EG. nifedipine used to treat some heart complaints
    • N - neurones - w-CTx-GVIA, produced by asian snail > death
    • P/Q - neurones - w-aga-IVA
    • R/T - neurones, heart? - Ni2+
  49. outline fast synaptic transmission
    • 1. calcium ions enter through calcium channels
    • 2. calcium ions bind to synaptotagmin
    • 3. vesicle brought close to membrane
    • 4. snare complex makes fusion pore
    • 5. transmitter released through pore

    at the motor nerve terminal this transmitter is ACh it then binds to the nACh on the post synaptic membrane changing the conformation of the protein
  50. describe myasthenia gravis and describe a type of drugs which work in a similar way
    • myasthenia gravis is a disease targetting nACh receptors, patients suffer with profound weakness which worsens with exercise, it is an autoimmune disease
    • drugs can also block this receptor by binding at the recognition site of ACh there are two types competitive blockers (tubocurorine) and depolarizing blockers (succinylcholine)
  51. why is it important to be able to control calcium ion concentration in our cells?
    too much calcium for too long is toxic to cells but many cellular events (enzyme activity, mobility, cell cycle progression, secretion...) rely on raised calcium we therefore need to be able to make it go up and back to normal.
  52. what mechanisms can we use to maintain calcium at its basal level?
    • when intracellular calcium rises it binds to calmodulin a signal transducer this then binds to PMCA a Ca-ATPase which removes calcium
    • NCX works best a resting potential and is an antiporter moving 3 sodium ions in for every 1 calcium ion it moves out
  53. what mechanisms can we use to raise intracellular calcium?
    depolarisation of the membrane opens VOCCs increasing the intracellular concentration

    ligands such as glutamate bind to receptor operated calcium channels such as NMDA and AMPA

    it can also be released for intracellular store in the S/ER by two mechanisms: 1. GPCR - IP3 acts on IP3 receptor on the S/ER. 2. CICR - calcium induced calcium release - calcium ions act on ryanodine receptors on the S/ER
  54. what mechanisms do we use to get rid of extra calcium so we can return to basal levels?
    there are 3 parts to this - termination of signal, calcium ion removal and calcium ion store refilling

    stores are refilled by recycling the released calcium SERCA (calcium/hydrogen antiporter) uses ATP to move calcium back into the S/ER. if this is not properly refilled the S/ER releases a depleted signal and the membrane protein SOC lets some calcium into the cell.

    mitochondria also play a part as a non rapidly releasable store
  55. how do cells communicate with each other?
    • hormones - endocrine signalling - between cells in different tissues via the circulation
    • neurotransmitters - synaptic signalling - specialised junctions in the nervous system
    • local chemical mediators - paracrine signalling - between adjacent cells in the same tissue

    most signalling molecules are hydrophillic but thyroid and steroid hormones are hydrophobic and travel on carrier proteins and bind to intracellular receptors
  56. what is a ligand?
    • a small molecule that binds specifically to a receptor site
    • can be an agonist, antagonist or partial agonist
  57. what is a receptor?
    a molecule that recognises a specific ligand or family of ligand and in response to ligand binding brings about regulation of a cellular process
  58. how are ACh receptors classified?
    • ACh receptors are affected by the binding of ACh
    • they are then divided based on other things that antagonise them into: nicotinic and muscarinic receptors
    • muscarinic receptors are then divided into M1, M2 and M3 which are coded for by different genes and each have a 'strongest' agonist
  59. what are the similarities and differences between receptors and enzymes?
    • similarities = specific, governed by shape, normally reversible
    • differences = affinity of ligand binding is stronger than substrate, ligand is not modified but substrate is.
  60. what are the roles of receptors?
    • signalling in response to hormones and chemical mediators
    • neurotransmission
    • control of gene expression
    • release of intracellular calcium stores
    • immune response
  61. what is the point of signal transduction?
    what are the four ways in which it happens?
    • most signalling molecules can't cross the plasma membrane and so must interact with a receptor at the cell surface, this binding is then transduced into an intracellular signal in one of 4 ways:
    • 1. ligand gated ion channels - fastest - agonist binding > conformational change > flow of ions down electrochemical gradient > electrical event at plasma membrane eg. nAChr, GABAr
    • 2. membrane bound receptors with intergral enzyme activity - agonist binding > conformational change > enzyme activation eg.tyrosine kinase linked receptor
    • 3. seven transmembrane domain receptors/G protein coupled receptors - coupled to effector molecule by a transducing molecule, a G protein. eg. mAChr, adrenoceptors, opiod/light/5-HT/purine receptors
    • 4. intracellular receptors - steroid hormones (cortisol/testosterone/oestrogen) and thyroid hormones (T3/4) pass through the plasma membrane and bind to receptors in the cytoplasm or nucleus > receptor dissociates from chaperone > binds to DNA sequence > regulates DNA expression
  62. extracellular signalling molecules are in very low concentration why does this not matter?
    the pathways allow for amplification
  63. what happens when NA binds B1 adrenoceptors on the cardiac pacemaker cells?
    what happens when ACh binds M2 receptors on cardiac pacemaker cells?
    inc. HR

    slows HR
  64. what happens when insulin acts on hepatocytes?

    what happens when glucagon acts on hepatocytes?
    glycogen formation

    glycogen breakdown
  65. what is pinocytosis?
    • the invagination of the plasma membrane to form a lipid vesicle
    • it allows for the uptake of impermeable extracellular solutes and the retrival of the plasma membrane it is divided into two forms fluid phase and receptor mediated endocytosis
  66. what are the basics of receptor mediated endocytosis?
    • specific uptake of substances into the cell due to binding of specific receptors
    • there are four modes:
    • 1. receptor recycled, ligand degraded, eg.LDL
    • 2. receptor recycled, ligand recycled, eg. transferrin
    • 3. receptor degraded, ligand degraded, eg insulin, immune complexes
    • 4. receptor transported, ligand transported, eg. maternal Im, IgA
  67. how is cholesterol taken up into the cells?
    • cholesterol transported as LDL and is studded with apoprotein B so when a cell wants cholesterol it puts out an apoprotein B receptor on its surface
    • the LDL binds over dents in the cell surface called coated pits
    • the pit invaginates taking the LDL into the cell
    • the clatherin coat is then driven off
    • the vesicle fuses with the endosome (CURL) which has a pH5 maintained by a H-ATPase which dissociates the ligand and the receptor
    • the receptor buds off and is recycled
    • LDL goes to the lysosome and cholesterol is released
  68. how are occupied insulin receptors taken up?
    • activated insulin receptors move to over a coated pit
    • they are invaginated and down regulated (degraded)
  69. what is transcytosis?
    in the liver large molecules are moved into the bile
  70. how do viruses and toxins exploit the endocytic pathways?
    membrane enveloped viruses and some toxins exploit these pathways eg cholera and diptheria toxin
  71. explain G protein coupled receptors?
    • 40% of prescribed drugs act on GPCRs
    • there are over 800 GPCRs in the genome all have the same basic structure - single polypeptide chain - 300-1200 aminoacids, 7TMDs, extracellular N terminal, intracellular C terminal
    • there are two regions for binding - the N terminus and 2/3 of the transmembrane spanning domains
    • they respond to many stimuli - sensory, neurotransmitters, ions, hormones...
  72. how do G protein coupled receptors change cellular activity?
    • when a GPCR is activated by the binding of an agonist it interacts with a G protein, the Gprotein is made up of an alpha, beta and gamma subunit
    • the alpha subunit binds GTP then seperates into alpha and beta-gamma, these can then interact with effectors
  73. give examples of GPCRs?
    • A/NA - Badrenoceptor - Gsa - +adenylcyclase - glycogenolysis, lipolysis
    • A/NA - a2-adrenoceptor - Gia - -adenylcyclase
    • A/NA - a1-adrenoceptor - Gqa - +phospholipase C
    • light - rhodopsin - Gta - +cyclic GMP phosphodiesterase - visual excitation
    • ACh - M3 - Gqa - +phospholipase C - smooth muscle contraction
    • ACh - M2 - Gia - -adenyl cyclase, +K channel - slow cardiac pacemaker
  74. how do GPCRs switch off?
    • GTPase within the alpha subunit hydrolyses GTP back to GDP
    • the subunits then rejoin - inactive heteromeric complex
  75. what diseases are caused by GPCR mutations?
    • loss of function of rhodopsin = retinitis pigmentosa > light blindness and tunnel vision
    • loss of function of V2 vasopressin receptor > nephrogenic diabetes insipidus
    • gain of function of LH receptor = familial male precocious puberty
  76. what drugs target GPCRs and how?
    • CNS - depression, schizophrenia, psychosis, migranes, parkinsons
    • CVS- hypertension, congestive heart failure, arrythmias, thrombosis
    • respiratory - asthma, COPD
    • GI - acid reflux, gastric ulcers, nausea
    • GU - overactive bladder, prostrate cancer, BPH
    • other - chronic pain, glucoma, rhinitis, motion sickness, anaphylaxis
  77. can we manipulate the GPCR cycle and if so how?
    cholera and pertussis toxin are used to inhibit and study the cycle
  78. explain the effector mechanism of G proteins
    • +adenyl cylase > cyclic AMP > PKA > vasodilation, lipolysis, glycogenolysis
    • + phospholipase C > PID2 > IP3 + DAG > contraction, fertilisation, SM constriction, +ve inotrophy, inc sweating
  79. what is the pharmaceutical process?
    • getting the drug into the patient
    • oral or parenteral - iv, im, rectal, sublingual, inhaler, topical
  80. what is the pharmokinetic process?
    • the drug reaching the site of action
    • if given orally must go through the liver first - 1st pass metabolism
  81. what is bio-availability?
    the amount of the drug that reaches the systemic circulation unchanged
  82. = AUC oral/AUC injected x100
  83. what is the therapeutic ratio?
    • max tolerated dose/max effective dose
    • lethal dose in 50%/effective dose in 50%
  84. how is drug distribution determined?
    • its protein binding interactions as only free drug exerts an effect
    • object drugs used at lower dose than albumin binding site eg warfin, phenytoin
    • precipitant drugs used at higher dose than albumin binding sites eg. asprin

  85. what is the equation for the rate of metabolism?
    vmax[c]/(km + c)
  86. describe first/zero order kinetics
    • first order - rate of decline is proportional to drug level
    • zero order - decline is constant
  87. how are drugs eliminated?
    what is the effect of liver/renal disease on these processes?
    • metabolism by the liver phase 1 and phase 2
    • phase 1 enzymes are induced eg. rifamppicn affects the oral contraceptive or they can be inhibited
    • excreted in urine but affect the pH
  88. liver disease causes problems with low therapeutic ratio drugs
    renal disease prolongues the half life and so lower maintainence doses are required
  89. what are common interactions with warfarin?
    • alcohol - inhibits metabolism
    • asprin/phenytoin/sulphonamides - displace from plasm proteins
  90. what is potency?
    • is a combination of efficacy and affinty
    • measured by giving effective dose of half maximal response
  91. what interactions can occur with drugs and receptors?
    many drugs work by mimicking or blocking ligands
  92. what does the ANS do?
    • motor innervation of the skeletal muscle
    • controls smooth muscle, exocrine and some endocrine glands
    • rate and force of heart
    • some influence on metabolic pathways
  93. describe the structure of the ANS?
    • always carries info from the CNS to the neuro-effector junction by two neurones in series
    • SYMPATHETIC - pre ganglionic bodies in lateral horn of grey matter and emerge from spinal cord in thoraco-lumbar region they synapse with post ganglionic neurones in paravertebral chains
    • PARASYMPATHETIC - emerge from spinal cord in cranial sacral regions the ganglia lie close to target organs and therefore the post sympathetic fibres are short
  94. what neurotransmitters are found in the ANS?
    • ACh and NA
    • all preganglionic fibres are cholinergic and release ACh which acts on nAChr on the post ganglionic cells
    • parasympathetic post ganglionic neurones are also cholinergic and ACh acts on mAChr
    • most sympathetic post ganglionic neurones are noradrenergic and release NA which acts on A1,A2,B1,B2 - Adrenoceptors

    sweat glands and piloerctor muscles are innervated by sympathetic fibres but are cholinergic
  95. what are the basic steps of neurotransmission?
    • 1. uptake of precusors
    • 2. synthesis of transmitter
    • 3. vesicular storage of transmitter
    • 4. depolarisation by propagated action potential
    • 5. influx of calcium ions
    • 6. exocytic release of transmitter
    • 7. diffusion to post synaptic membrane
    • 8. interaction with post synaptic receptors
    • 9. inactivation of transmitter
    • 10. reuptake of transmitter or degradation of products
  96. describe the specific steps of cholinergic transmission
    • 1. uptake of precusors
    • 2. synthesis of ACh from acetyl-CoA and choline
    • 3. vesicular storage of transmitter
    • 4. depolarisation by propagated action potential
    • 5. influx of calcium ions
    • 6. exocytic release of transmitter
    • 7. diffusion to post synaptic membrane
    • 8. interaction with post synaptic receptors
    • 9. inactivation of transmitter by cholinesterase breakdown
    • 10. reuptake of choline
  97. what drugs act on cholinergic transmission?
    • nicotinic cholinoceptor antagonists
    • muscarinic cholinoceptor agonists - treat glucoma
    • muscarinic cholinoceptor antagonists - anasthetic premed, reduce bronchial and salivary secretions, bronchioconstriction
    • cholinesterase inhibitors - reverse anasthetic, treat myasthenia gravis
  98. NA synthesis
    tyrosine + tyrosine hydroxylase > DOPA +dopa decarboxylase > dopamine + dopamine beta hydroxylase > noradrenaline + phenyl ethanol amine N-methyl tranferase > adrenaline
  99. describe the specific steps of adrenergic transmission
    • 1. uptake of precusors
    • 2. synthesis of NA from tyrosine
    • 3. vesicular storage of dopamine then synthesised into NA (cytoplasmic NA suseptible to breakdown by MAO)
    • 4. depolarisation by propagated action potential
    • 5. influx of calcium ions
    • 6. exocytic release of transmitter
    • 7. diffusion to post synaptic membrane
    • 8. interaction with post synaptic receptors
    • 9. inactivation of transmitter
    • 10. reuptake by high affinity uptake 1 and low affinity uptake 2
  100. what drugs act on adrenergic transmission?
    • alpha-methyl tyrosin - inhibits tyrosine hydroxylase - blocking NA synthesis- clinically treat phaeochromocytoma
    • alpha - methyl dopa - taken up by neurones and converted into alpha methyl NA poorly metabolised so accumulates and released as false transmitter can be used to treat hypertension
  101. name some adrenergic agonists and antagonists
    • B1 agonist - dobutamine - positive inotrophy and chronotrophy - treat circulatory shock
    • B2 agonist - salbutamol - reversing bronchiconstriction in asthmatics
    • A1 agonist - nasal decongestant or local vasoconstrictor
    • A2 agonist - anti-hypertensive

    • A antagonist - peripheral vasodilator - treat PVD
    • A1 antagonist - hypertension - can > postural hypotension/impotence
    • B antagonist - propanol/atanalol - treat hypertension, MI, angina
  102. what is the clinical significance of receptor regulation in opiate dependence?
    • activation of the m-opiod receptor is associated with analgesia, euphoria, sedation
    • we have natural opioids - endophins
    • dependence > receptors become up regulated and relative under dosing occurs > body releases excessive NA > withdrawal symptoms - tachycardia, sweating etc.
  103. what is the clinical significance of receptor regulation in phaeochromacytoma?
    • tumour of adrenal medulla
    • causes intermittent secretion of catcholamines > increased sympathetic activity > high BP, sweating etc.
  104. what is the clinical significance of receptor regulation in asthma?
    • M3-ACh-constriction
    • B1-NA- dilation
    • be careful with B blocker interventions
  105. what is the clinical significance of receptor regulation in pregnancy?
    • effects of catecholamines:
    • alpha-adrenoceptors = contraction
    • bets-adrenoceptors = relaxation

    oestrogen > up regulation of alpha-adrenoceptors > labour
  106. what is the clinical significance of receptor regulation in thyrotoxicosis?
    • TSH antibodies act as an agonist to TSH receptor > excess release of T4
    • in young people > tremour, weight loss, sweating, palpatations
    • in old people > atrial fibrilation