MnR Flashcards
What is the function of a β2-adrenoceptor-selective agonist
β2-adrenoceptor-selective agonists (e.g.salbutamol, salmeterol) are used in asthma to reverse bronchoconstriction. The β2- adrenoceptor-selectivity of such agents limits possible cardiovascular side-effects (e.g. positive inotropic and chronotropic actions)
How does cholesterol decrease membrane fluidity at high temperatures and increase fluidity at low temperatures?
At high temperatures where increased random movement of the fatty acid side chains and hence increased fluidity would occur, cholesterol by its interaction with the phospholipid reduces the movement of the fatty acid side chains at a given temperature, thereby enhancing phospholipid packing and reducing membrane fluidity.
At low temperatures where phospholipids would normally pack together into the ‘crystalline form’ gel state and reduce membrane fluidity, cholesterol by intercalating with the phospholipid molecules reduces the ability to form ordered packed crystals and thereby increases membrane fluidity.
What is hereditary elliptocytosis?
a common defect is a spectrin molecule that is unable to form heterotetramers resulting in fragile elliptoid cells
Parasympathetic nerve terminals at neuroeffector junctions, i.e. ‘presynaptic receptors’
Predominant receptor subtype?
Major Physiological action?
Predominant receptor subtype?
M2
Major Physiological action?
Feedback inhibition of neurotransmitter ACh release
List 3 histological features of skeletal muscle
Multiple nuclei
Nuclei along striations
Striations
Mutations affecting the LDL-receptor
- Receptor deficiency. Mutations that prevent expression of LDL receptor.
- Non-functional receptor. No binding of LDL. Normal coated pits and internalization.
- Receptor binding normal. No internalization due to a deletion in the C-terminal of the receptor that makes the interaction with the coated pits. LDL-receptors are found distributed over the whole cell surface in these patients.
During the heartbeat, myocardial Ca2+ channels open and result in a substantial increase in Ca2+ permeability.
In which direction does the Ca2+ flow?
Inwards, down the electrochemical gradient.
What would happen to the membrane potential if there was an increase in the permeability of the membrane to K+ ions?
the membrane will hyperpolarise and the membrane potential will move closer to EK
Describe the effects of sympathetic and parasympathetic innervation on the eye
Innervation of the iris: The iris has radial and sphincter muscles.
Sympathetic stimulation causes contraction of the radial muscles and pupil dilation.
Parasympathetic stimulation causes contraction of the sphincter muscles and pupil constriction.
What is known of the distribution of ion channels in myelinated nerve?
Sodium channels are limited to the node of Ranvier. Potassium channels may be present in the node, but are also present in the paranodal region, immediately to the side of the node. Some authorities argue that these then prevent re-entrant excitation of the node by preventing action potential spread under the myelin sheath
What is the class of acetylcholine receptor found at the parasympathetic neuroeffector junction?
Muscarinic receptors are found at the parasympathetic neuroeffector junction.
What occurs during the generation of an action potential?
- depolarization to threshold triggers the opening of many voltage-gated Na + channels
- the influx of Na + produces the rapid upstroke of the action potential (membrane potential moves towards ENa )
- this depolarization causes inactivation of Na + channels and opening of voltage- gated K+ channels
- Na+ influx stops and the increased K+ efflux leads to repolarization (membrane potential moves towards EK )
- relatively little ions move and the Na/K ATPase is NOT involved in action potential repolarization
State the effect of parasympathetic and sympathetic innervation and the receptors that mediate the effects, on the sweat glands
Parasympathetic = stimulates secretion
Sympathetic = stimulates secretion
Receptor = α1, muscarinic
Give an example of an agent which interferes with the release of acetylcholine.
Botulinum toxin (a potent toxin released by the bacterium Clostridium botulinum) interferes with the process of Ca2+-stimulated exocytosis markedly inhibiting vesicle fusion and ACh release. Although Botulinum toxin is most often associated with poisoning, it does have a specific therapeutic usage, with local injection of the toxin being used in the treatment of certain muscle dyskinesias.
Explain the terms spatial summation and temporal summation
Spatial summation- increase in the number of motor units innervating a muscle fibre at one time
Temporal summation- increase in the frequency of action potentials from a single motor unit towards a muscle.
What are the two permitted modes of mobility of proteins in a lipid bilayer?
- Fast axial rotation.
- Fast lateral diffusion within the plane of the bilayer.
State the effect of parasympathetic and sympathetic innervation and the receptors that mediate the effects, on the SA node in the heart
Parasympathetic = decreases heart rate
Sympathetic = increases heart rate
Receptor = β1
What is the effect of increased parasympathetic discharge in the heart?
- In the heart, the sino-atrial node, atria and atrioventricular node receives parasympathetic innervation, whilst the ventricular muscle does not
- the predominant effect of increased parasympathetic discharge is to decrease the rate of contraction (negative chronotopy) rather than to affect the force of contraction.
- Although there is little parasympathetic innervation of vascular smooth muscle, airways and GItract smooth muscle is richly innervated.
State the effect of parasympathetic and sympathetic innervation and the receptors that mediate the effects on the uterus in a non-pregnant women
Parasympathetic = Parasympathetic fibres of the uterus are derived from the pelvic splanchnic nerves (S2-S4) and localised to the cervix
Sympathetic = relaxation
Receptor = β2
What is MS?
This is a disease of the immune system where myelin is destroyed in certain areas of the CNS. This can have dramatic effects on the ability of previously myelinated axons to conduct action potentials properly.
Sinoatrial node
Predominant receptor subtype?
Major Physiological action?
Predominant receptor subtype?
M2
Major Physiological action?
Decrease inrate of spontaneous depolarisation to generate action potentials. Negative chronotropy
What are first order pharmacokinetics?
Constant FRACTION of drug eliminated in unit time.
Rate of elimination increases as drug concentration increases.
Half life can be defined.
Describe what is meant by the term saltatory conduction
Saltatory conduction is the mode of conduction of the nervous impulse found in myelinated nerve fibres.
Saltatory means leaping or jumping conduction; the action potential is set up only at nodes of Ranvier and an active node (undergoing an action potential) raises the next resting node of Ranvier to threshold
State the effect of parasympathetic and sympathetic innervation and the receptors that mediate the effects on adipose tissue
Parasympathetic = None
Sympathetic = stimulates lipolysis
Receptor = β3
Describe how the erthyrocyte cytoskeleton is structured, and which components are disturbed in hereditary spherocytosis.
The erythrocyte cytoskeleton is a network of spectrin and actin molecules. Spectrin is a long, floppy rod- like molecule. α1 and β1 subunits wind together to form an antiparallel heterodimer and two heterodimers then form a head-to-head association to form a heterotetramer of α2β2. These rods are crosslinked into networks by short actin protofilaments (~14 actin monomers), and band 4.1 and adducin molecules which form interactions towards the ends of the spectrin rods. The spectrin-actin network is attached to the membrane through adapter proteins. Ankyrin (band 4.9) and band 4.1 link spectrin and band 3 protein and glycophorin A, respectively. Attachment of integral membrane proteins to the cytoskeleton restricts the lateral mobility of the membrane protein.
Name the mechanisms which transduce an extracellular hydrophilic signal into an intracellular event.
- Membrane-bound receptors with integral ion channels
- Membrane-bound receptors with integral enzyme activity
- Membrane-bound receptors which couple to effectors through transducing proteins
- Intracellular receptors for hydrophobic ligands
Which noradrenalin receptor is found in the ventricles?
β1
What type of fibre arrangement does the bicep have?
Fusiform
The erythrocyte cytoskeleton is a network of what?
Spectrin and actin molecules.
What determines whether a nerve terminal is “dopaminergic” (releases dopamine) or “noradrenergic” (releases noradrenaline)?
- The first two enzymes in the pathway – tyrosine hydroxylase and DOPA decarboxylase – are both cytosolic
- whereas the enzyme which converts dopamine to noradrenaline – dopamine β-hydroxylase – is present within the synaptic vesicles.
Name the TWO major enzymes responsible for inactivation of noradrenaline?
Monoamine oxidase (MOA)
Catechol-O-methyl transferase (COMT)
What are the consequences of increasing parasympathetic tone in the eye? Might this be beneficial in decreasing intraocular pressure?
- Increased parasympathetic tone causes contraction of the sphincter muscle of the iris, narrowing the pupil.
- This improves drainage of the aqueous humor by relieving folding of the iris over the canal of Schlemm.
- This alleviates raised introcular pressure in glaucoma.
- This effect can be mimicked by muscarinic agonists such as pilocarpine, which is used clinically.
State the effect of parasympathetic and sympathetic innervation and the receptors that mediate the effects n the bladder wall.
Parasympathetic = Contraction
Sympathetic = Relaxation
Receptor = β2
What are the 5 general functions of biological membranes?
- Continuous highly selective permeability barrier.
- Allows control of the enclosed chemical environment
- Communication - control the flow of information between cells and their environment
- Recognition - signalling molecules, adhesion proteins, immune surveillance
- Signal generation in response to stimuli - electrical, chemical
What unwanted side effects limit the usefulness of Muscarinic antagonist?
- Decreased secretion: Salivary, lacrimal, bronchial and sweat gland secretions are inhibited, even at very low doses of muscarinic antagonists resulting in uncomfortably dry mouth and skin.
- Although at low concentrations muscarinic antagonists can cause a centrally-mediated paradoxical decrease in heart rate, higher doses cause the predictable mild tachycardia resulting from inhibition of resting vagal tone.
- Through effects on muscles of the urinary tract, muscarinic antagonists can cause urinary retention, particularly in the elderly.
- Central effects of muscarinic antagonists are perhaps the factor which most limits the utility of this class of agent. Thus, even at low doses, a muscarinic antagonist which can enter the brain will cause restlessness
Apart from glucose, what other metabolites use the sodium gradient for their uptake into cells against the concentration gradient?
Amino acids. There is a family of known transporters for different groups of related amino acids
State the effect of parasympathetic and sympathetic innervation and the receptors that mediate the effects, on the AV node in the heart
Parasympathetic = decreases conduction velocity
Sympathetic = increases conduction velocity
Receptor = β1
How long does it take to achieve a steady state of drug?
During repeated drug administration, a new steady state is achieved in 5 half lives.
Predict what the clinical consequences of high EK might be
This results in cardiac arrhythmia which may result in the heart stopping (probably due to sodium channel inactivation).
Explain the difference between the two types of skeletal muscle contraction
Isotonic-where the muscle changes length under a constant force
Isometric- where the muscle maintains a constant length whilst exerting a force
Indicate how local anaesthetics act to block action potentials of peripheral nerves. Name one such drug.
Local anaesthetics act to block Na+ channels. They normally block channels only when they are open, so that the block is use-dependent. Procaine is such a drug
What are zero order pharmacokinetics?
Rate of elimination is a constant AMOUNT.
Rate does not increase as drug concentration increase.
What are the stages of transmitter release?
- Ca2+ entry through Ca2+ channels
- Ca2+ binds to synaptotagmin
- Vesicle brought close to membrane
- Snare complex make a fusion pore
- Transmitter released through this pore
What is the function of a α1-adrenoceptor-selective antagonist
α1-adrenoceptor-selective antagonists (e.g. doxazosin) and β1- adrenoceptor-selective antagonists (e.g. atenolol) are used to treat a number of cardiovascular disorders, including hypertension.
How can membranes become specialized?
Physical changes, i.e. microvilli
Compositional changes i.e. voltage‐gated channels in synapses
What occurs during the RRP?
Sodium channels are recovering from inactivation, the excitability returns to normal as the number of channels in the inactivated channels decrease.
State the effect of parasympathetic and sympathetic innervation and the receptors that mediate the effects on the uterus in a pregnant woman
Parasympathetic = parasympathetic stimulation causes cervical fibers contraction
Sympathetic = contraction
Receptor = α1
The cholera toxin binds to the CFTR channel and keeps it open. Explain how this will lead to diarrhoea
Toxin binds, leads to chloride secretion, sodium follows, and ultimately so does water leading to dehydration
What is glycosylation?
Adding of a sugar to a protein
When during development does myelination occur?
In different nerve fibres during the period between the 4th month of fetal life and the end of the first year
Bronchi
Predominant receptor subtype?
Major Physiological action?
Predominant receptor subtype?
M3 (M2)
Major Physiological action?
Contractile (spasmogenic) response
In myasthenia gravis what protein is the autoimmune attack directed towards, what is its normal function and what effect does this have?
Nicotonic AchR- it is a ligand-gated ion channel on the post-synaptic membrane actvated by Ach, a neurotransmitter. Loss of nAchR’s leads to reduced end-plate potentials in the muscles or other post-synaptic sites where nAchR’s are present.
What might be the effect of treating a demyelinated nerve fibre with an agent that blocks voltage-gated potassium channels?
Since blockage of voltage-gated potassium channels will prolong the action potential, it will increase the chance that an active node can excite the next resting node across the internode that has been damaged by demyelination
Ach is the neurotransmitter utilized at the neuromuscular junction. What receptors does Ach bind to and what are the differences between these receptors?
Nicotinic AchR- ligand gated ion channel
Muscarinic AchR- coupled to a signalling cascade through G-proteins so is much slower
Fast and slow Ach synapses
List 3 histological features of smooth muscle
Nuclei in the centre of the cell
Cigar shaped cells
No striations
Explain how the insulin receptor is recycled and degraded.
- Insulin binding probably induces a conformational change in the insulin receptor that allows it to be recognised by the coated pit.
- In the endosome insulin remains bound to the receptor and the complex is targeted to the lysosomes for degradation
- This mechanism allows for the reduction in the number of insulin receptors on the membrane surface (down-regulation) which desensitises the cell to a continued presence of high circulating insulin concentrations.
What diagnostic test could you use to diagnose myasthenia gravis?
serum anti-AChR antibodies
List 3 histological features of cardiac muscle
Central nuclei
Striations
Intercalated discs
Branching cells
Glands
Predominant receptor subtype?
Major Physiological action?
Predominant receptor subtype?
M3
Major Physiological action?
Stimulation of glandular secretions
Describe the mechanism of action of local anaesthetics.
They act by temporaily binding to voltage-gated sodium channels and block the S6 alpha-helix of the protein which is an intracellular domain.
If the desired effect is to increase the stimulation of muscarinic receptors, what alternative non-receptor strategy can be adopted? Which agents are used clinically?
An alternative to using muscarinic receptor agonists is to inhibit the breakdown of acetylcholine using an acetylcholinesterase inhibitor. Physostigmine and ecothiopate are used clinically in eye drops to treat glaucoma.
What type of cell, with a specialised function does the CFTR channel reside?
Epithelial cells and membrane transport function, connected to an external surface.
What two factors determine whether ion flow involves passive or active transport?
Concertation ratio Membrane potential
Which adrenoreceptor is found at the SA node?
β1
What occurs during the ARP?
Nearly all sodium channels are in the inactivated state
What are the consequences of an increased Cl‐ conductance for the membrane potential?
Cl‐ conductance by producing membrane hyperpolarisation reduces excitability.
N.B. Volume regulation by Cl‐ channels in non‐excitable tissues
Describe how ions move as a consequence of channel opening during the action potential.
- Initial depolarization leads to opening of Na+ channels, so that Na+ ions enter the cell, causing further depolarization.
- As K+ channels open, K+ ions flow through them out of the cell, returning the membrane potential to its negative resting value
Bladder
Predominant receptor subtype?
Major Physiological action?
Predominant receptor subtype?
M1/M3
Major Physiological action?
Contractile response
Name 2 antagonists of nAchRs.
Tubocurarine
Succinylcholine
Describe what is recorded during electromyography.
The recordings made are effectively compound action potentials within the muscle. As motor unit recruitment increases in response to increasing load, so the amplitude of the recording increases.
What are the four permitted modes of mobility of lipids in a lipid bilayer?
- Intra-chain motion - kink formation in the fatty acyl chains
- Fast axial rotation.
- Fast lateral diffusion within the plane of the bilayer.
- Flip-flop - movement of lipid molecules from one half of the bilayer to the other on a one for one exchange basis.
Describe the immediate consequences of a sudden increase/decrease of the extracellular sodium concentration.
Cells will shrink when extracellular sodium concentration increases suddenly and swell when the extracellular sodium concentration decreases because of the change in extracellular osmotic pressure
Which neurones in the ANS are responsible for innervating respiratory rate and heart rate?
Thoracic nerves T1/2/3/4- sympathetic
Cranial nerve X- parasympathetic
What are the two classes of drugs?
- Class I drug (object drug) is used at dose lower than number of albumin binding sites
- Class II drug (precipitant) drug is used at doses greater than number of binding sites, and thus displaces the Class I drug
Name 3 possible reasons why a carbohydrate may be attached to an integral membrane protein.
Lock the orientation of the protein
preventing flip-flop
Cellular recognition Immune recognition
Which factors affect the propagation of an action potential?
the diameter of the axon
presence of myelin
The action potential is often described as all-or-nothing.
What does this mean?
Once the threshold for firing an action potential is reached, an AP of fixed amplitude is produced; the AP is not graded with the size of the stimulus.
Which channels do what?
Opening Na+ or Ca2+ channels will depolarize cells.
Opening K+ or (usually) Cl- channels will hyperpolarize cells.
State the effect of parasympathetic and sympathetic innervation and the receptors that mediate the effects in the veins
Parasympathetic = None
Sympathetic = Vasocontriction and vasodilation (adrenaline)
Receptor = α1, β2
Describe an example of a drug that mimic the effects of hereditary spherocytosis
Cytochalasin drugs cap the end of polymerising actin filamaents which can alter the deformability of erythrocytes.
Describe the fundamental differences in composition between intracellular and extracellular fluids.
Extracellular fluid accounts for about 1/3 of the fluid in the human body and has more ionic components than intracellular fluid. The two main types of extracellular fluid are blood plasma and interstitial fluids.
Intracellular fluid, also called cytosol, makes up the other 2/3 of the fluids in the human body. This fluid contains more amino acids and proteins than extracellular fluid.
What contribution does the Na+‐K+‐ATPase make to the maintenance of the resting membrane potential?
Although electrogenic, the Na+‐K+‐ATPase makes only a small direct contribution to membrane potential i.e. < ‐ 5 mV.
Which ion channels are involved in generating an action potential?
Voltage-dependent sodium channels
voltage-dependent potassium channels
Name 3 agonists and 3 antagonists of mAchRs.
Agonists: acetylcholine, oxotremorine , muscarine
Antagonists: atropine, scopolamine, haloperidol
How does insulin stimulate the rate of uptake of glucose into adipose tissue and skeletal muscle?
Recruits GLUT‐4 glucose transporters from internal vesicular membranes to the plasma membrane to increase the transport capacity of the membrane
What are the most important membrane transport mechanisms involved in the control of intracellular Na+, K+ and Ca2+ concentrations?
- Plasma membrane Na+, K+‐ATPase maintains low [Na+]i + high [K+]i.
- Plasma membrane and sarcoplasmic reticulum Ca2+‐ATPases maintain low [Ca2+]i under resting conditions.
- Na+‐Ca2+‐exchanger may contribute to the restoration of [Ca2+]i following a rise in [Ca2+]i
What is Hereditary Spherocytosis?
spectrin levels may be depleted by 40 - 50%
The cells round up and become much less resistant to lysis during passage through the capillaries and are cleared by the spleen
What prevents the efflux of glucose from cells in tissues such as adipose and skeletal muscle when the circulating glucose concentration falls to resting levels in the post‐absorptive period after a meal?
Glucose is rapidly converted to glucose‐6‐phosphate on entering the cell. Thus, the intracellular glucose concentration never rises high enough to reverse the concentration gradient
How does the uptake of glucose from the blood into adipose, brain, liver and skeletal muscle cells differ that in intestinal and kidney epithelial cells?
Glucose concentration gradient favours uptake.
Glucose enters by facilitated transport down the glucose concentration gradient via glucose transporters.
A family of glucose transport proteins (GLUT‐1‐7) exists with different kinetic properties to suit the needs of individual tissues
What are the two phases of metabolism?
Phase I - Oxidation, reduction, hydrolysis
Phase II - Conjugation (glucuronide, acetyl, methyl, sulphate)
What is the fate of noradrenaline removed from the synaptic cleft? Can noradrenaline be re-packaged for re-use?
The recaptured noradrenaline can undergo one of two fates: firstly, it can be taken up into vesicles and therefore re-used in a further cycle of neurotransmission.
Treatment of asthma is generally mediated by an agonist at which type of receptor?
β2 adrenoceptor
