MnR

Question 1

What is the function of a β2-adrenoceptor-selective agonist

Answer 1

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)

Question 2

How does cholesterol decrease membrane fluidity at high temperatures and increase fluidity at low temperatures?

Answer 2

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.

Question 4

What is hereditary elliptocytosis?

Answer 4

a common defect is a spectrin molecule that is unable to form heterotetramers resulting in fragile elliptoid cells

Question 5

Parasympathetic nerve terminals at neuroeffector junctions, i.e. ‘presynaptic receptors’

Predominant receptor subtype?

Major Physiological action?

Answer 5

Predominant receptor subtype?

M2

Major Physiological action?

Feedback inhibition of neurotransmitter ACh release

Question 6

List 3 histological features of skeletal muscle

Answer 6

Multiple nuclei

Nuclei along striations

Striations

Question 7

Mutations affecting the LDL-receptor

Answer 7

1. Receptor deficiency. Mutations that prevent expression of LDL receptor.
2. Non-functional receptor. No binding of LDL. Normal coated pits and internalization.
3. 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.

Question 8

During the heartbeat, myocardial Ca2+ channels open and result in a substantial increase in Ca2+ permeability.

In which direction does the Ca2+ flow?

Answer 8

Inwards, down the electrochemical gradient.

Question 9

What would happen to the membrane potential if there was an increase in the permeability of the membrane to K+ ions?

Answer 9

the membrane will hyperpolarise and the membrane potential will move closer to E_K

Question 10

Describe the effects of sympathetic and parasympathetic innervation on the eye

Answer 10

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.

Question 11

What is known of the distribution of ion channels in myelinated nerve?

Answer 11

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

Question 12

What is the class of acetylcholine receptor found at the parasympathetic neuroeffector junction?

Answer 12

Muscarinic receptors are found at the parasympathetic neuroeffector junction.

Question 13

What occurs during the generation of an action potential?

Answer 13

• 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

Question 14

State the effect of parasympathetic and sympathetic innervation and the receptors that mediate the effects, on the sweat glands

Answer 14

Parasympathetic = stimulates secretion

Sympathetic = stimulates secretion

Receptor = α1, muscarinic

Question 15

Give an example of an agent which interferes with the release of acetylcholine.

Answer 15

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.

Question 16

Explain the terms spatial summation and temporal summation

Answer 16

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.

Question 17

What are the two permitted modes of mobility of proteins in a lipid bilayer?

Answer 17

1. Fast axial rotation.
2. Fast lateral diffusion within the plane of the bilayer.

Question 18

State the effect of parasympathetic and sympathetic innervation and the receptors that mediate the effects, on the SA node in the heart

Answer 18

Parasympathetic = decreases heart rate

Sympathetic = increases heart rate

Receptor = β1

Question 19

What is the effect of increased parasympathetic discharge in the heart?

Answer 19

• 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.

Question 20

State the effect of parasympathetic and sympathetic innervation and the receptors that mediate the effects on the uterus in a non-pregnant women

Answer 20

Parasympathetic = Parasympathetic fibres of the uterus are derived from the pelvic splanchnic nerves (S2-S4) and localised to the cervix

Sympathetic = relaxation

Receptor = β2

Question 21

What is MS?

Answer 21

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.

Question 22

Sinoatrial node

Predominant receptor subtype?

Major Physiological action?

Answer 22

Predominant receptor subtype?

M2

Major Physiological action?

Decrease inrate of spontaneous depolarisation to generate action potentials. Negative chronotropy

Question 23

What are first order pharmacokinetics?

Answer 23

Constant FRACTION of drug eliminated in unit time.

Rate of elimination increases as drug concentration increases.

Half life can be defined.

Question 24

Describe what is meant by the term saltatory conduction

Answer 24

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

Question 25

State the effect of parasympathetic and sympathetic innervation and the receptors that mediate the effects on adipose tissue

Answer 25

Parasympathetic = None Sympathetic = stimulates lipolysis Receptor = β3

Question 26

Describe how the erthyrocyte cytoskeleton is structured, and which components are disturbed in hereditary spherocytosis.

Answer 26

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.

Question 27

Name the mechanisms which transduce an extracellular hydrophilic signal into an intracellular event.

Answer 27

* 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

Question 28

Which noradrenalin receptor is found in the ventricles?

Answer 28

β1

Question 29

What type of fibre arrangement does the bicep have?

Answer 29

Fusiform

Question 30

The erythrocyte cytoskeleton is a network of what?

Answer 30

Spectrin and actin molecules.

Question 31

What determines whether a nerve terminal is "dopaminergic" (releases dopamine) or "noradrenergic" (releases noradrenaline)?

Answer 31

* 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.

Question 32

Name the TWO major enzymes responsible for inactivation of noradrenaline?

Answer 32

Monoamine oxidase (MOA) Catechol-O-methyl transferase (COMT)

Question 33

What are the consequences of increasing parasympathetic tone in the eye? Might this be beneficial in decreasing intraocular pressure?

Answer 33

* 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.

Question 34

State the effect of parasympathetic and sympathetic innervation and the receptors that mediate the effects n the bladder wall.

Answer 34

Parasympathetic = Contraction Sympathetic = Relaxation Receptor = β2

Question 35

What are the 5 general functions of biological membranes?

Answer 35

1. Continuous highly selective permeability barrier. 2. Allows control of the enclosed chemical environment 3. Communication - control the flow of information between cells and their environment 4. Recognition - signalling molecules, adhesion proteins, immune surveillance 5. Signal generation in response to stimuli - electrical, chemical

Question 36

What unwanted side effects limit the usefulness of Muscarinic antagonist?

Answer 36

1. 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. 2. 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. 3. Through effects on muscles of the urinary tract, muscarinic antagonists can cause urinary retention, particularly in the elderly. 4. 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

Question 37

Apart from glucose, what other metabolites use the sodium gradient for their uptake into cells against the concentration gradient?

Answer 37

Amino acids. There is a family of known transporters for different groups of related amino acids

Question 38

State the effect of parasympathetic and sympathetic innervation and the receptors that mediate the effects, on the **AV node in the heart**

Answer 38

Parasympathetic = decreases conduction velocity Sympathetic = increases conduction velocity Receptor = β1

Question 39

How long does it take to achieve a steady state of drug?

Answer 39

During repeated drug administration, a new steady state is achieved in **5** **half lives**.

Question 40

Predict what the clinical consequences of high E_K might be

Answer 40

This results in cardiac arrhythmia which may result in the heart stopping (probably due to sodium channel inactivation).

Question 41

Explain the difference between the two types of skeletal muscle contraction

Answer 41

**Isotonic**-where the muscle changes length under a constant force **Isometric**- where the muscle maintains a constant length whilst exerting a force

Question 42

Indicate how local anaesthetics act to block action potentials of peripheral nerves. Name one such drug.

Answer 42

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

Question 43

What are zero order pharmacokinetics?

Answer 43

Rate of elimination is a constant AMOUNT. Rate does not increase as drug concentration increase.

Question 44

What are the stages of transmitter release?

Answer 44

* 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

Question 45

What is the function of a α1-adrenoceptor-selective antagonist

Answer 45

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.

Question 46

How can membranes become specialized?

Answer 46

Physical changes, i.e. microvilli Compositional changes i.e. voltage‐gated channels in synapses

Question 47

What occurs during the RRP?

Answer 47

Sodium channels are recovering from inactivation, the excitability returns to normal as the number of channels in the inactivated channels decrease.

Question 48

State the effect of parasympathetic and sympathetic innervation and the receptors that mediate the effects on the uterus in a pregnant woman

Answer 48

**Parasympathetic** = parasympathetic stimulation causes cervical fibers contraction **Sympathetic** = contraction **Receptor** = α1

Question 49

The cholera toxin binds to the CFTR channel and keeps it open. Explain how this will lead to diarrhoea

Answer 49

Toxin binds, leads to chloride secretion, sodium follows, and ultimately so does water leading to dehydration

Question 50

What is glycosylation?

Answer 50

Adding of a sugar to a protein

Question 51

When during development does myelination occur?

Answer 51

In different nerve fibres during the period between the 4th month of fetal life and the end of the first year

Question 52

Bronchi Predominant receptor subtype? Major Physiological action?

Answer 52

**Predominant receptor subtype?** M3 (M2) **Major Physiological action?** Contractile (spasmogenic) response

Question 53

In myasthenia gravis what protein is the autoimmune attack directed towards, what is its normal function and what effect does this have?

Answer 53

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.

Question 54

What might be the effect of treating a demyelinated nerve fibre with an agent that blocks voltage-gated potassium channels?

Answer 54

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

Question 55

Ach is the neurotransmitter utilized at the neuromuscular junction. What receptors does Ach bind to and what are the differences between these receptors?

Answer 55

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

Question 56

List 3 histological features of smooth muscle

Answer 56

Nuclei in the centre of the cell Cigar shaped cells No striations

Question 57

Explain how the insulin receptor is recycled and degraded.

Answer 57

* 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.

Question 58

What diagnostic test could you use to diagnose myasthenia gravis?

Answer 58

serum anti-AChR antibodies

Question 59

List 3 histological features of cardiac muscle

Answer 59

Central nuclei Striations Intercalated discs Branching cells

Question 60

**Glands** Predominant receptor subtype? Major Physiological action?

Answer 60

**Predominant receptor subtype?** M3 **Major Physiological action?** Stimulation of glandular secretions

Question 61

Describe the mechanism of action of local anaesthetics.

Answer 61

They act by temporaily binding to voltage-gated sodium channels and block the S6 alpha-helix of the protein which is an intracellular domain.

Question 62

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?

Answer 62

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.

Question 63

What type of cell, with a specialised function does the CFTR channel reside?

Answer 63

Epithelial cells and membrane transport function, connected to an external surface.

Question 64

What two factors determine whether ion flow involves passive or active transport?

Answer 64

Concertation ratio Membrane potential

Question 65

Which adrenoreceptor is found at the SA node?

Answer 65

β1

Question 66

What occurs during the ARP?

Answer 66

Nearly all sodium channels are in the inactivated state

Question 67

What are the consequences of an increased Cl‐ conductance for the membrane potential?

Answer 67

Cl‐ conductance by producing membrane hyperpolarisation reduces excitability. N.B. Volume regulation by Cl‐ channels in non‐excitable tissues

Question 68

Describe how ions move as a consequence of channel opening during the action potential.

Answer 68

* 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

Question 69

**Bladder** Predominant receptor subtype? Major Physiological action?

Answer 69

**Predominant receptor subtype?** M1/M3 **Major Physiological action?** Contractile response

Question 70

Name 2 antagonists of nAchRs.

Answer 70

Tubocurarine Succinylcholine

Question 71

Describe what is recorded during electromyography.

Answer 71

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.

Question 72

What are the four permitted modes of mobility of lipids in a lipid bilayer?

Answer 72

1. Intra-chain motion - kink formation in the fatty acyl chains 2. Fast axial rotation. 3. Fast lateral diffusion within the plane of the bilayer. 4. Flip-flop - movement of lipid molecules from one half of the bilayer to the other on a one for one exchange basis.

Question 73

Describe the immediate consequences of a sudden increase/decrease of the extracellular sodium concentration.

Answer 73

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

Question 74

Which neurones in the ANS are responsible for innervating respiratory rate and heart rate?

Answer 74

Thoracic nerves T1/2/3/4- sympathetic Cranial nerve X- parasympathetic

Question 75

What are the two classes of drugs?

Answer 75

* **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

Question 76

Name 3 possible reasons why a carbohydrate may be attached to an integral membrane protein.

Answer 76

Lock the orientation of the protein preventing flip-flop Cellular recognition Immune recognition

Question 77

Which factors affect the propagation of an action potential?

Answer 77

the diameter of the axon presence of myelin

Question 78

The action potential is often described as all-or-nothing. What does this mean?

Answer 78

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.

Question 79

Which channels do what?

Answer 79

Opening Na+ or Ca2+ channels will depolarize cells. Opening K+ or (usually) Cl- channels will hyperpolarize cells.

Question 80

State the effect of parasympathetic and sympathetic innervation and the receptors that mediate the effects in the veins

Answer 80

Parasympathetic = None Sympathetic = Vasocontriction and vasodilation (adrenaline) Receptor = α1, β2

Question 81

Describe an example of a drug that mimic the effects of hereditary spherocytosis

Answer 81

Cytochalasin drugs cap the end of polymerising actin filamaents which can alter the deformability of erythrocytes.

Question 82

Describe the fundamental differences in composition between intracellular and extracellular fluids.

Answer 82

**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.

Question 83

What contribution does the Na+‐K+‐ATPase make to the maintenance of the resting membrane potential?

Answer 83

Although electrogenic, the Na+‐K+‐ATPase makes only a small direct contribution to membrane potential i.e. \< ‐ 5 mV.

Question 84

Which ion channels are involved in generating an action potential?

Answer 84

Voltage-dependent sodium channels voltage-dependent potassium channels

Question 85

Name 3 agonists and 3 antagonists of mAchRs.

Answer 85

**Agonists**: acetylcholine, oxotremorine , muscarine **Antagonists**: atropine, scopolamine, haloperidol

Question 86

How does insulin stimulate the rate of uptake of glucose into adipose tissue and skeletal muscle?

Answer 86

Recruits GLUT‐4 glucose transporters from internal vesicular membranes to the plasma membrane to increase the transport capacity of the membrane

Question 87

What are the most important membrane transport mechanisms involved in the control of intracellular Na+, K+ and Ca2+ concentrations?

Answer 87

* 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

Question 88

What is Hereditary Spherocytosis?

Answer 88

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

Question 89

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?

Answer 89

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

Question 90

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?

Answer 90

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

Question 91

What are the two phases of metabolism?

Answer 91

Phase I - Oxidation, reduction, hydrolysis Phase II - Conjugation (glucuronide, acetyl, methyl, sulphate)

Question 92

What is the fate of noradrenaline removed from the synaptic cleft? Can noradrenaline be re-packaged for re-use?

Answer 92

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.

Question 93

Treatment of asthma is generally mediated by an agonist at which type of receptor?

Answer 93

β2 adrenoceptor