WEEK 2 Flashcards
Define the 2 types of organisation of smooth muscle (unitary/visceral or multiunitary), giving examples of each.
- UNITARY/VISCERAL
- sheets of electrically coupled cells which act in unison
- often spontaneously active
- e.g. found in the walls of most viscera of body (GI tract, ureters, uterus, many BVs) - MULTIUNITARY
- discrete bundle of cells which are densely innervated & contract only in response to the innervation
- each fibre can contract independently
- e.g. vas deferens, ciliary muscles of eye, piloerector muscles.
What is the Actin : Myosin ratio in smooth muscle?
15 : 1
Describe the filament organisation of smooth muscle.
Large numbers of actin filaments are attached to ‘dense bodies’. Some of these bodies are attached to the cell membrane. Others are dispersed inside the cell. Some of the membrane-dense bodies of adjacent cells are bonded together by intercellular protein bridges. It is mainly through these bonds that the force of contraction is transmitted from one cell to the next.
Interspersed among the actin filaments in the muscle fiber are myosin filaments. These have a diameter more than twice that of the actin filaments
Briefly recall the steps of smooth muscle contraction.
- Initiated by calcium from the extra cellular fluid or the sarcoplasmic reticulum
- Calcium binds to calmodulin
- Ca-calmodulin-MLCK complex leads to phosphorylation of MLC(Myosin light chain) (requires 1 ATP)
- MLC is part of a myosin head
- The phosphorylated myosin head binds to actin & the power stroke occurs automatically
- A second ATP is required to release the myosin head from actin.
What are the 3 sources of calcium in smooth muscle?
Voltage dependant ion channels
Ligand gated ion channels
Intracellular stores
Briefly recall the steps of smooth muscle relaxation.
- Calcium concentration dips below a critical level, due to it being pumped out of the cell, or into the SR.
- Calcium is then released from calmodulin
- MLCP(Myosin light chain phosphatase) removes phosphate from MLC => detachment of myosin head from actin filament => relaxation
What does (i) Metabolism (ii) Anabolism and (iii) Catabolism, mean?
(i) means by which organisms extract energy from their environment, and use it to synthesise large molecules
(ii) large molecules built from smaller molecules (small->large)
(iii) large molecules broken down in to smaller molecules (large->small)
Explain the meaning of the thermodynamic term “free energy”. And the equation that goes along with this.
ΔG=ΔG^o+RT loge ([C][D] / [A][B])
ΔG = free energy change for the reaction with reactants at the conc given ΔG^o = standard free energy change (when all reactants at conc of 1.0M)
What is phosphorylation?
Adding phosphate to a molecule
What is ATP needed for? (Hint: there’s 4)
- Body movement (via muscular contraction)
- Cellular movements (via cytoskeleton)
- Active transport
- Synthesis of large molecules
Explain the ways in which enzymic reactions can be regulated.
- Changes in the amounts of substrates and products of pathways
- Changes in amounts of key enzymes
- Changes in activity of key enzymes
- allosteric changes
- effects of substrate and downstream products
- covalent modification of enzymes (e.g. phosphorylation)
Describe the structure of the myosin molecule.
2 identical subunits:
- 2 globular head regions
- 2 long chain alpha helical regions
What is the molecular structure of the actin filament?
Constructed from individual G-actin molecules
Two chains are wound into an alpha helix (F-actin)
What is the role of each regulatory protein? (Hint: there’s 3)
TROPONIN COMPLEX
- Troponin T (TnT) - interacts with tropomyosin
- Troponin I (TnI) - inhibits myosin ATP-ase
- Troponin C (TnC) - calcium binding protein
What is rigor mortis? Explain the molecular basis.
The stiffening of skeletal muscles after death.
- occurs 3-4 hours after death
- max after 12 hours
Cells accumulate calcium.
Because ATP is absent, cross-bridges can bind to actin, but the cross-linkages are irreversible.
What are the 3 additional sources of ATP used by muscle?
Creatine phosphate
Oxidative phosphorylation (aerobic)
Anaerobic glycolysis
Why can’t aerobic respiration meet the energy demands of muscle?
Limited O2 and nutrient supply
Enzyme turnover rates are too slow
What are the 3 factors used to differentiate muscle fibre types?
- Speed of contraction
- Capacity to make ATP
- Resistance to fatigue
What is the meaning of Glycolysis and where does this process occur?
Breakdown of glucose to smaller molecules, producing ATP
Takes place in the cytoplasm of cells.
During glycolysis, what is glucose broken into?
2 molecules of Pyruvate(3C), and a relatively small amount of ATP generated (net gain of 2)
Recall the major steps of Glycolysis.
- Phosphorylation - traps glucose in cell, as glucose-6-P is ionised and unable to cross the membrane (consumes ATP)
2.Isomerisation - glucose-6-P -> fructose-6-P (both have same formula)
3.Phosphorylation - hexose diphosphate formed that can be split into 2 phosphorylated 3C compounds (consumes ATP)
4.Cleavage & Isomerisation - 2 phosphorylated 3C compounds. Allowing dihydroxyacetone-P ->glyceraldehyde-3-P (which can be metabolised)
5.Oxidative Phosphorylation - Glyceraldehyde-3-P is simultaneously oxidised & phosphorylated
Hydrogen & electrons from gylceraldehyde-3-P are passed to NAD+ - Transfer of Phosphate - where 1 ATP is produced from conversion of 1,3-Biphosphoglycerate to 3-Phosphoglycerate
- Molecular Rearrangment - the phosphate group is moved from one position to another (from 3 to 2)
- Dehydration - the change from 2-Phosphoglycerate to Phosphoenol pyruvate favours the transfer of phosphate to ATP
- Transfer of Phosphate - 1 ATP produced converting to pyruvate
Recall the importance of nicotinamide adenine dinucleotide (NAD).
Vit B3 (niacin) provides the nicotinamide part of NAD+ A lack of niacin causes: - pellagra - dermatitis - alopecia - glossitis - weakness - ataxia
Why is lactic acid produced in anaerobic respiration?
NADH builds up because NAD+ cannot be regenerated, if this situation persisted, glycolysis would halt.
NADH is re-oxidised by reducing pyruvate to lactate
What are three enzymes that catalyse steps in glycolysis ? State what their function is.
- Hexokinase
- catalyses glucose -> glucose-6-P - Phosphofructokinase
- catalyses: fructose-6-P -> fructose-1,6-biphosphate - Pyruvate Kinase
- catalyses: phosphoenolpyruvate -> pyruvate
Of these, phosphofructokinase is the rate limiting:
o High [ATP] allosterically inhibits the enzyme
o Low pH inhibits the enzyme (lactate accumulation)
o High [citric acid] inhibits
o High [fructose-6-P] stimulates the enzyme
What are the 3 ways to block neuromuscular transmission?
- Pre-synaptically - by inhibiting ACh synthesis (rate limiting step is choline uptake)
- Pre-synaptically - by inhibiting ACh release
- Post synaptically - by interfering with the actions of Ach on the receptor
What is meant by depolarising and non-depolarising blockers?
- Non-depolarising blockers:
- competitive antagonist of the of nicotinic ACh receptor at the NMJ e.g. tubocuracaine, atracurium - Depolarisingblockers:
- agonists of nicotinic ACh receptor at NMJ e.g. suxamethonium.
Describe the 2 phases in which a depolarising blocker can occur.
PHASE 1:
- muscle fasiculations observed, then blocked
- repolarisation inhibited (K+ leaked from cells = hyperkalaemia)
-V gated Na+ cells kept inactivated
PHASE 2:
- prolonged/increased exposure to drug
- ‘desensitisation blockade’ (depolarisation cannot occur, even in the absence of the drug)
What are the clinical uses of neuromuscular blocking drugs?
- endotrachial intubation
- during surgical procedures (decreases amount of GA needed so safer)
- in intensive care (mechanical ventilation)
- electroconvulsive therapy
What is acetylcholinesterase (ACh.E)?
- true cholinesterase, specific for hydrolysis of ACh
- found in conducting tissue & RBC’s
- is bound to the BM in the synaptic cleft
What are anticholinesterase drugs?
- are all inhibitors of cholinesterase enzymes
=> there’s an larger availability of ACh at NMJ by decreased degradation - increases the duration of the activity of ACh at NMJ
- more ACh to compete with non-depolarising blockers
What are the effects of anticholinesterases on (i) the central nervous system and (ii) the autonomic nervous system?
CNS:
- initial excitation with convulsions
- unconsciousness & respiratory failure
AUTONOMIC:
Salivation Bradycardia
Lacrimation Hypotension
Urination Bronchoconstriction
Defecation Pupillary constriction(miosis)
Gastrointestinal upset
Emesis
What are the clinical uses of anticholinesterases?
Anaesthesia -reverse non-depolarising muscle blockade Myasthenia Gravis -increase NM transmission Glaucoma - decrease intraocular pressure Alzhiemer's -enhance the cholinergic transmission in the CNS
What is sugammadex?
Is a selective relaxant binding agent (SRBA)
- it reverses the effects of rocuronium and vecuronium
Name the 8 carpal bones (and know where they are located in relation to each other)
Scaphoid Lunate Triquetrum Pisiform Trapezium Trapezoid Capitate Hamate
What is the anatomical snuff box?
Prominent when thumb is abducted.
EPL & EPB are what make up the snuff box.
The radial artery, branches of radial nerve, and the cephalic vein lie within the snuff box
What is the extensor retinaculum?
It holds the extensor tendons in place, in synovial sheaths, against the posterior aspects of the radius and ulna.
The synovium may become inflamed with over-use, causing painful tenosynovitis.
Cystic swellings that communicate with a synovial sheath may occur too.
Name the tarsal bones (and know where they are located in relation to each other)
Calcaneus (heel) Talus (body, neck, head) Cuboid Navicular Cuneiforms (1,2,3)
What vitamin is FAD formed from? List the deficiencies of said vitamin.
Vitamin ribolflavin (vit B2) Lesions of the mucous membranes - cracked sore lips & corners mouth - similar lesions genital area - tongue: swollen, tender, magenta
During the citric acid cycle how many (i) CO2 (ii) GTP (iii) NADH (iv) FADH2 are produced overall?
(i) 2
(ii) 1
(iii) 3
(iv) 1
What is the first step in the TCA cycle?
Condensation of the acetyl group of acetyl CoA with the keto acid oxaloacetate
What are the three large protein complexes that make up the respiratory chain?
NADH-Q reductase
Cytochrome reductase
Cytochrome oxidase
What does movement of electrons down the respiratory chain generate? What is this used to drive?
H+ ion (pH) gradient across the inner mitochondrial membrane
The resulting electrochemical gradient is used to drive ATP synthesis by way of ATP synthase
How many molecules are produced from 1 molecule of NADH and 1 molecule of FADH2 respectively?
NADH - 3 ATP
FADH2 - 2 ATP
What is the major form in which fuels are stored? How much energy can this form produce?
Lipids
- weight-for-weight, triglycerides produce about 6 times as much energy as glycogen
What is the difference between a diacyl glycerol and a triacyl glycerol?
In a diacylglycerol, one of the groups of glycerol is not esterified
Why are ketone bodies made?
Acetyl-CoA formed in the breakdown of fatty acids cannot enter the citric acid cycle since oxaloacetate becomes depleted because the liver converts it to pyruvate to produce glucose (gluconeogenesis)
=> acetyl CoA is converted to ketone bodies
Why are some amino acids used as a metabolic fuel? What does an amino acid yield when it is deaminated?
They are not needed to make new proteins and cannot be stored
NH4 and a keto acid
What is transamination?
When an amino acid cannot release its amino group as NH4, but instead pass their amino group to a keto acid
The resulting keto acid can then be fed into glycolsis/CAC, whilst the resulting amino acid can be deaminated and used similarly
What is gluconeogenesis? Where does this process mainly occur?
Formation of glucose from non-carbohydrate stores
similar to glycolysis in reverse
Liver
Describe the metabolic properties of the brain.
Glucose is the only fuel used by the brain
Cannot store glucose or glycogen and so needs a constant blood supply of it
Brain accounts for 60% of the bodies glucose usage
In times of starvation, the brain can use ketone bodies as a fuel source
Cannot use fatty acids because of the blood-brain barrier
What are the metabolic properties of skeletal muscle?
Uses glucose, fatty acids AND ketone bodies
When at rest, mainly fatty acids are used
Has large glycogen reserves (3/4 of total body glycogen)
When active, the rate of glycolysis outpaces the rate of the citric acid cycle and so pyruvate is converted to lactate
When muscle protein is being broken down, what do many amino acids do?
They convert their amino group to pyruvate, in order to form alanine
Alanine enters blood and in the liver can be converted to pyruvate (glucose)
=> liver takes some of the metabolic burden from muscles
What is the main function of adipose tissue?
To synthesise and store triglycerides
And to release fatty acids and glycerol in times of need
In adipose tissue, what does the availability of glucose determine?
The rate at which fatty acids are esterified
What are the metabolic properties of the liver?
Co-operates with brain, muscle and adipose
Hepatic portal system: ensures liver has access to nutrients absorbed by gut
Can store & release glucose. Makes glucose from: lactate, alanine & glycerol
If fuel available: synthesises and esterifies fatty acids, secretes them into blood as VLDL
During fasting: generates ketone bodies
Describe the fed state.
ANABOLIC
Uses nutrient molecules which provide energy stores or growth and maintenance of tissues.
Some molecules are used immediately as energy is needed
Describe the fasted state.
CATABOLIC
Calls on energy stores - which in turn become depleted
What cells secrete insulin? What state does insulin drive and what does it stimulate?
Beta cells
Drives the fed state
Stimulates: glycogen synthesis in liver & muscle
Glucose uptake in muscle & adipose
Glycolysis, and => fatty acid synthesis in liver
Triglyceride formation in fat tissue
Protein synthesis in muscle
What cells secrete glucagon? What state does glucagon drive and what does it stimulate?
Alpha cells
Fasted state
Main target is liver where is stimulates:
- release of glucose, from glycogen
- gluconeogenesis, which => inhibits incorporation into glycogen
What determines whether the body is in the fasted or fed state?
The balance between the levels of insulin and glucagon
What is the function of adrenaline and noradrenaline?
Drive breakdown of triglycerides & glycogen
Mainly on muscle not liver, => lowering glucose uptake by muscle (FA released by adipose used as fuel)
Increases glucagon secretion, inhibiting insulin secretion
Describe the first days of starvation.
Carbohydrate stores only last a day of less so blood [glucose] tends to fall
Muscle uses FA (sparing glucose stores for the brain)
Liver uses fats from adipose and pyruvate, lactate and alanine from muscle to make as much glucose as possible for brain
Describe the later stages of starvation.
After 3 days - ketone bodies formed in liver
- brain becomes tolerant of lowered blood [glucose]
=> now able to use ketone bodies, and this use gradually increases over weeks
- less glucose used => need for amino acids decreases
=> reduction in the rate that muscle is broken down
What are the two types of diabetes mellitus? Describe them.
Type 1 - Insulin dependent - beta cells are destroyed => decrease insulin secreted Treatment = inject insulin Type 2 - Non insulin dependent - tissue insensitive to insulin - less severe
Why is untreated diabetes associated with excessive urination?
In glomeruli of kidney, glucose leaves blood & passes into urine with ions and other relatively small molecules
Normally transporters in the proximal convoluted tubule reabsorb all glucose and return it to the blood
In diabetes if blood [glucose] rises beyond certain level, amount that passes into the kidney tubules so great that transporters cannot remove it all
This glucose adds to osmotic strength of urine
=> harder for the kidney to reabsorb water from
urine
=> urine volume greatly increased (explains why urine of diabetic contains glucose)
Severe cases: acidic ketone bodies appear in the urine (ketoacidosis) adding slightly to osmotic strength.
What can long term high blood [glucose] damage?
Blood vessels (polyneuropathy)
Eyes (retinal BVs)
Kidneys (urine infection, scarring & swelling glomeruli => protein in urine)
Cardiovascular diseases (result of narrowing BVs)
What is sensitivity and how is it calculated? (NOTE: lecture on screening)
= how well the test picks up having the disease
= no. results where disease detected in people with the disease / no. people with the disease
What is specificity and how is it calculated? (NOTE: lecture on screening)
= how well the test detects NOT having the disease
= no. ‘normal’ results where disease is NOT detected in people without the disease / no. people without the disease
What is the positive predictive value and how is it calculated? (NOTE: lecture on screening)
= how reliable is the test result which shows the disease is present?
= no. people with the disease & +ve test result / no. people with a +ve test result
What is the negative predictive value and how is it calculated? (NOTE: lecture on screening)
= how reliable is the test result in showing the disease is not present?
= no. people w/out disease and a -ve test result / no. people with a -ve test result.
