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Phase 1 IMMS > Cell Ultrastructure > Flashcards

Cell Ultrastructure Flashcards

1
Q

What can be caused by abnormal signalling/membrane transport?

A

include:
53. Oedema
54. Palpitations/abnormal heart rhythm
55. Raised blood pressure
65. Diarrhoea
91. Abnormal serum sodium
92. Raised serum calcium

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2
Q

What is a cell?

A

Fundamental functional unit of a tissue

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3
Q

What makes up a cell?

A
  1. Lysosomes:
    •Cell’s dustbin
  2. Mitochondria:
    •TCA cycle
    •Oxidative phosphorylation
    ➢Maternal inheritance only
  3. Smooth Endoplasmic Reticulum:
    •No ribosomes
    •Site of lipid synthesis
    •Some drug metabolism
  4. Microtubules:
    •Give structure to cell
  5. Rough Endoplasmic Reticulum:
    •Studded with ribosomes
    •Site of protein synthesis
  6. Golgi body:
    •Mediates protein sorting to specific sites
  7. Ribosomes:
    •Translate mRNA into protein
  8. Plasma membrane
    •Keeps stuff in/out
    •Selectively permeable
  9. Nucleus
    Genome:
    •Instructions…
    •Inherited disease
    •Cancer

Cytosol?

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4
Q

??

A

Anti-bodies hormones?
Receptor ion channels?

Membrane vesicles:
●Intra-cellular tran
- endo/exocytosis

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5
Q

Why are membranes and their proteins needed?

A
  1. Cell signalling
    ➢Source of lipid precursors
  2. Cell polarisation
    ➢Epithelia – this lecture
  3. Compartmentalisation
    ➢Ionic gradients – next lecture
    ●Diffusion (Nernst potential)
    ●Membrane potential
  4. Tightly regulated
  5. Disease disrupts this
    ➢Heart disease
    ➢Kidney failure
    ➢Cancer
    ➢Inflammation
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6
Q

Glycerophospholipid

A

Fatty acid tails:
•Non-polar
•Hydrophobic
•Saturated C-C bonds
•Unsaturated cis C=C bonds
➢Kinks hydrophobic tail
•Significant variation in length

Glycerol backbone (3C)
Phosphate group
-ve charge at physiological ph

One of either…
➢Serine (PS - phosphatidyl-serine)
➢Choline (PC - phosphatidyl-choline)
➢Inositol (PI - phosphatidyl-inositol)
➢Ethanolamine - PE (phosphatidyl-ethanolamine)
➢Sphingomyelin - SM

Glycerophospholipids
•Hydrophobic and hydrophilic
•Amphipathic molecules

Phospholipid head
- polar charged
- hydrophilic

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7
Q

Glycerophospholipid

A

Fatty acid tails:
•Non-polar
•Hydrophobic
•Saturated C-C bonds
•Unsaturated cis C=C bonds
➢Kinks hydrophobic tail
•Significant variation in length

Glycerol backbone (3C)
Phosphate group
-ve charge at physiological ph

One of either…
➢Serine (PS - phosphatidyl-serine)
➢Choline (PC - phosphatidyl-choline)
➢Inositol (PI - phosphatidyl-inositol)
➢Ethanolamine - PE (phosphatidyl-ethanolamine)
➢Sphingomyelin - SM

Glycerophospholipids
•Hydrophobic and hydrophilic
•Amphipathic molecules

Phospholipid head
- polar charged
- hydrophilic

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8
Q

What is the structure of the lipid bilayer?

A

Leaflet specific orientation
•Leaflet “flip”
➢Thermodynamically unfavourable

Outer:
•Sphingomyelin
•Enriched for PC

Inner:
•Enriched for PE
•PS and PI majority in inner leaflet

•PS – presence in outer leaflet is “eat me” signal for apoptosis

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9
Q

What is the fluidity of the bilayer?

A

Membrane fluidity is important…
➢Movement of phospholipids and proteins
➢Facilitates inter- and intra-cellular signalling (phosphatidylinositol)
➢Temperature- and structure-dependent phase transitions.

Liquid-ordered (raft)
•Highly ordered
•Relatively fluid

Solid gel
➢Highly ordered
➢Limited lateral mobility

Liquid-disordered
➢Low density packing
➢High lateral mobility

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10
Q

What are the integral membrane proteins?

A

Many sorts
➢Channels, pores, structural

• Defined secondary structure
➢a-helix in transmembrane region
➢Hydrophobic amino acids interface with hydrophobic phospholipid tail
➢Membrane helps maintain 3D structure

K2P§ K+ channel

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11
Q

What are anti-bodies to phospholipids?

A

Anti-phospholipid syndrome
•Systemic auto-immune disease.
•Anti-bodies bind to b2-Glycoprotein-1 on cell membranes
➢Initiate inappropriate blood clotting (thrombosis)
•Significant cause of pregnancy morbidity and early miscarriage

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12
Q

What is epithelia like?

A

Epithelia…
•Require polarisation of plasma membrane – apical vs basolateral surfaces
•Permits cell-specific function – secretion/absorption
•Strongly adhere to neighbours – tight junctions

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13
Q

What is the structure and layers of epithelia?

A
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14
Q

What are epithelia like?

A

Epithelia…
•Require polarisation of plasma membrane – apical vs basolateral surfaces
•Permits cell-specific function – secretion/absorption
•Strongly adhere to neighbours – tight junctions
•Three examples:
➢parietal cell (gastric pits)
➢intestinal epithelium
➢nephron

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15
Q

What occurs in parietal acid secretion?

A

On base lateral membrane
Osmosis
ECF
Duct lumen
Parietal cell
Omeprazol

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16
Q

How is substrate movement affected by water?

A

Substrate movement across membranes occurs with movement of water…

Sodium:glucose co-transport (symport) - basis of oral rehydration therapy

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17
Q

What is the nephron like?

A

The Nephron…
•Morphology and permeability of tubular epithelial cells changes along the tubule
•Reflects specific function of each aspect of tubule:

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18
Q

How is membrane function affected by environmental changes?

A

pH
➢Both extremes damage protein
➢Inhibits cell function

Critical role for acid:base homeostasis
Plasma Ca2+
Cell membrane
Excitability/permeability

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19
Q

How is membrane function affected by environmental changes?

A

pH
➢Both extremes damage protein
➢Inhibits cell function

Critical role for acid:base homeostasis
Plasma Ca2+
Cell membrane
Excitability/permeability

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20
Q

How are calcium concentrations tightly regulated?

A

Total serum calcium measured clinically (ionised [Ca2+] + unionised [Ca])

Serum Calcium:
•45% Free ionised Ca2+
➢Biologically active
➢Change Ca2+ (active): Ca (inactive) ratio with no change in total calcium
Acidosis
●fewer Ca2+ ions bound to plasma proteins
●H+ ions buffered by albumin instead
Alkalosis
●more Ca2+ bound to plasma proteins
●fewer H+ ions on albumin
➢Alkalotic patients more susceptible to hypocalcaemic tetany
➢Due to increased neuronal membrane Na+ permeability

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21
Q

How does temperature affect membrane function?

A

Temperature
➢Too cold – proteins slow down; membrane less fluid
➢Too hot – proteins denature; increased membrane

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22
Q

Effects of temperature on membrane function?

A

Heat exhaustion core temp >37°C but ≤40°C
Heat stroke core temp ≥ 40°C
Dehydration…

Everything slows down ‘umbles’
Lowest survivable core temp 13.7°C

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23
Q

What are the signs of hypothermia?

A

Signs of hypothermia: progressively

  • Shivering - increased pulse, BP and respiratory rate with shivering/pulse, BP and respiratory rate slowly reduce until undetectable
  • cardiac symptoms - atrial fibrillation, ventricular fibrillation inductively by rough handling, asystole
  • neurological symptoms - listlessness and confusion, reduced consciousness, unconsciousness
24
Q

How is SAN AP regulated?

A

Hypothermia
• depolarization rate of cardiac pacemaker cells
➢Bradycardia (not vagally mediated)
•Abnormal heart rhythms
➢Fibrillation (atrial and ventricle)

25
Q

What is Hypovolaemia is and the lethal triad?

A
  1. Hypothermia
    Decreased plasma
  2. Acidosis
    Plasma PH
  3. Coagulopathy
    Core temperature
26
Q

What are membranes like?

A

Phospholipid bilayer, proteins, cholesterol,
•Temperature sensitive
•Leaflet-specific use of phospholipids
•Main proteins in correct 3D orientation
➢Facilitates rapid interaction (signal transduction)
•Proteins
➢Integral/peripheral
➢Glycosylated
➢Many functions

27
Q

What is epithelia like?

A

Epithelia
•Need polarisation of apical/basolateral surfaces
➢Gastro-intestinal epithelium
➢Differential solute permeability based on function (nephron)
•Compartmentalises cell functions

28
Q

What is membrane permeability like?

A

Phospholipid bilayer…
•Fluidity modified by
➢C=C bonds
➢Cholesterol
➢temperature

29
Q

What is the cell membrane permeable to?

A

Freely Permeable…
•Water (aquaporins)
•Gases
➢(CO2, N2, O2)
•Small uncharged polar molecules
➢(Ammonia, urea, ethanol)

30
Q

What is the cell membrane impermeable to?

A

Impermeable to…
•Ions
➢(Na+, K+, Cl-, Ca2+ etc.)
•Charged Polar molecules
➢(ATP, Glucose-6-phosphate)
•Large uncharged polar molecules
➢(Glucose)

31
Q

What are the three main types of carriers in membrane proteins?

A
  1. Uniport
    ➢Single substance
    ●Glucose via Glut-1
    ●Passive
  2. Antiport
    ➢Two substances in opposite directions
    ●3Na+/2K+ ATPase
    ●Energy from ATP hydrolysis

3.Symport
➢Two (or more) substance in the same direction
●Na+/Glc nutrient transport
●Indirectly from ATP hydrolysis
●Ion gradient used

32
Q

What are some examples of membrane transport?

A

Simple diffusion
➢Blood gases, water
➢NH3, Urea, free fatty acids
➢Ketone bodies

●Facilitated diffusion
➢Glucose (glc; hexose sugars)
➢GLUT family

●Primary Active transport
➢Ions (Na+, K+, Ca2+, H+, HCO3-)
➢Water-soluble vitamins
➢Energy direct from ATP

●Ion Channels
➢Many sorts…
➢Voltage-gated
➢“Leak” channels

●Secondary active transport
➢Ions (renal tubule; fluid balance)
➢Symporters (Na+ + X)
➢Indirect energy from ion gradient

●Pino- / phago-cytosis
➢Vesicles

33
Q

What are ion channels like?

A

Many sorts (Na+, K+, Cl-…)
•Integral membrane protein

•Defined secondary structure
➢a-helix
➢Hydrophobic amino acids interface with hydrophobic phospholipid tail
➢Hydrophilic pore for ion passage

•Selective
➢Charge
➢Ion size

•Gated (usually)

34
Q

What are the cell membrane receptors?

A

Signal Transduction

•Internalise extra-cellular signal…
➢First message into second message

35
Q

What are cell surface and nuclear receptors?

A

Signal Transduction
•Pharmaceutical targets…

Nuclear steroid receptors (NSRs)
•Direct effect on gene expression
•ER – tamoxifen
•PR – mifepristone
•AR – testosterone
•GR – cortisol; dexamethasone
•MR – aldosterone; spironolactone

Neurotransmission (NTRs)
•AchR – Muscarinic cholinergic blockade – atropine
•GABA – benzodiazipines
•Seretonin (5-HT3) - ondansatron

Ion channels
•Ca 2+ - nifedipine
•Na+ - Amiloride
•K+ - Amiodarone

GPCRs - Many sorts, many effects
•Membrane-bound steroid receptors
•In-direct effect on gene expression
•E – cardiovascular effects?
•P – uterine function/sperm function

Growth factors (GFRs)
•Tyrosine kinases mechanism
•EGFR – pertuzumab (Perjeta) – breast cancer
•VEGF - bevacizumab (Avastin) – ovarian cancer
•Growth Hormone – (Genetropin)
•Insulin; IGFs

36
Q

What are GPCRs like?

A

GPCR –
•Ubiquitous (>800 sequences)
•>50% of all drugs mimic or inhibit various GPCR
•Significant drug target
•How do they work?

GPCR – six parts:
•Receptor – gives primary specificity
•Three G-proteins – a, b, g
➢Ga further specificity
•Enzyme to modulate second messenger
➢(e.g. cAMP)
•Enzyme to terminate signal
➢Phosphodiesterase

37
Q

What is Ga subunit and fluid secretion?

A

+ve; makes cAMP:
•b2 agonists, PGE2 via EP2 receptor (uterine relaxation)
•Many intra-cellular actions

Lungs - Activates CFTR
•Hydrates mucus
•Mucociliary staircase

Cystic fibrosis
•DF508 – inactivation of CFTR
• Cl- secretion
•Airway/intestinal mucus underhydrated
•Reduced mucociliary clearance

Intestinal epithelium
•Cholera toxin – permanent activation of Gas and AC
• Cl- secretion (CFTR) – osmotic drag
•Significant fluid

38
Q

What is Ga subunit and fluid secretion?

A

+ve; makes cAMP:
•b2 agonists, PGE2 via EP2 receptor (uterine relaxation)
•Many intra-cellular actions

Lungs - Activates CFTR
•Hydrates mucus
•Mucociliary staircase

Cystic fibrosis
•DF508 – inactivation of CFTR
• Cl- secretion
•Airway/intestinal mucus underhydrated
•Reduced mucociliary clearance

Intestinal epithelium
•Cholera toxin – permanent activation of Gas and AC
• Cl- secretion (CFTR) – osmotic drag
•Significant fluid loss

39
Q

How does Ga subunit determine second messenger?

A

-ve; prevents cAMP:
•a2 adrenergic agonists – Ergometrine
●(uterine contraction)
•a, m, d, k, opioid receptors
•PGE2 via EP1 and EP3 receptors
●Misoprostol (uterine contraction)
•M2 ACh receptors
+ve; makes IP3 and DAG (membrane phosphatidyl inositol):
•Oxytocin receptor, PGF2 via FP2a receptor
●(uterine contraction; severe PPH; Carboprost)
•M3 ACh receptors

40
Q

What is ion transport and RMP like?

A

Important driving force for trans-membrane ion transport
•Three components
➢Diffusional force (hight to low)
➢Electrical force (+ve to –ve)
➢Electrochemical (combination of both)

•Each ion carries a small charge when it diffuses across a membrane
➢ion diffusion potential
➢“Electrical force required across a membrane to counterbalance chemical diffusion forces of a given ion through that membrane”
➢NO net diffusion of that ion

•Collective ion diffusion potentials contribute to membrane potential

41
Q

What is the diffusion potential in trans-membrane ion gradients?

A
42
Q

What is the diffusion potentials driving force?

A

Nernst equation ?

Describes ion diffusion work done (ratio) – chemical driving force
Equilibrium: diffusional (chemical) and electrical forces balance
At

43
Q

Ion gradients?

A

Convention dictates:
•Extracellular fluid potential = 0 mV (Reference)
•Diffusion potential is that on intra-cellular membrane

Hyperpolarised - (less +ve)
Polarised (more +ve)
Hyperpolarised - more -ve/Cl- can cause depolarisation too

44
Q

What is the RMP like (Em)?

A

Each ion carries a small charge when it diffuses across a membrane
➢ion diffusion potential
•Collective ion diffusion potentials contribute to membrane potential
•Must consider ion diffusion potential collectively…

Goldman- Hodgkin-Katz equation
Don’t need to learn

45
Q

What is the MP (Em) like?

A

•Ion conductance (permeability) is key determinant of Em
•Stable in most cells (but sensitive to ionic imbalance)
•Transient variability in excitable tissue
➢Ventricular myocytes Em ~ -90mV
•Permeability dependant on
➢Channel numbers
➢Channel gating
•Change ion permeability…
➢Change Em

46
Q

What is the RMP like?

A

High K+ permeability (10; leak channels, -94.5 mV)
•Low Na+ permeability (0.05;+61.8 mV)
•Low Cl- permeability (0.45; -69.27 mV)
➢Na+/K+ together -90.6 mV
•Cl-
➢negligible contribution to resting Em (Cl- ~1.8 mV)

•Na+/K+ ATPase contributes small voltage to Em (~10 mV)
•K+ primary driving force in setting resting Em
➢Muscle damage, Type-II diabetes, renal patients - [K+]E can be out of range

47
Q

What is K+ membrane potential like?

A

Serum [K+] range: 3.5 - 5.3 mmol/l (increased K+ - hyperkalaemia)
Em less -ve (tending to depolarisation)
Reaches threshold more easily
Cell depolarisation more likely (weaker)
‘Car misfiring’
Decreased SAN firing/ bradycardia

Decreased [K+]E (Clinically – hypokalaemia):
•Em more –ve (tending to hyperpolarisation)
•Disrupts various K+ channels
•Abnormal heart rhythms (arrhythmias)

Kidneys and adrenal steroids
•Major role in K+ homeostasis
•Renal failure – don’t excrete excess K+
•Adrenal gland problems (Conn’s – too much aldosterone)

48
Q

Hyperkalemia and therapeutic membrane transport?

A

Insulin + dextrose
•Insulin activates Na+/H+ antiport
• [Na+]I drives Na+/K+ ATPase
•Cells take up excess K+ ions; [K+]E
•What about the dextrose?

49
Q

What occurs in regular ventricular AP?

A

Phase 0:
•Depolarisation
➢Fast Na+ channels

Phase 1: K+ leak – partial repolarisation

Phase 3 – K+ efflux - repolarisation

Phase 4:
•Diastolic resting potential ~ -90 mV

Phase 4: Return to resting potential
•Ca2+/Na+ channels close
• K+ permeability

Phase 2 – Plateau /contraction
•Slow Ca2+ channels (L-type) open
• K+ permeability – no repolarisation

50
Q

What occurs in regular ventricular AP?

A

Phase 0:
•Depolarisation
➢Fast Na+ channels

Phase 1: K+ leak – partial repolarisation

Phase 2 – Plateau /contraction
•Slow Ca2+ channels (L-type) open
• K+ permeability – no repolarisation

Phase 3 – K+ efflux - repolarisation

Phase 4:
•Diastolic resting potential ~ -90 mV

Phase 4: Return to resting potential
•Ca2+/Na+ channels close
• K+ permeability

51
Q

Role of digoxin in ventricular AP?

A
52
Q

Role of digoxin in ventricular AP?

A
53
Q

How does ischameia affect ventricular AP?

A

Ischaemia:
Hypoxia - [ATP]I
Opens KATP channel
•EM less –ve (~-55mV) (4)
•Depolarises easily
•Fast Na+ channels inhibited ~ -55mV

Slow Ca2+-mediated depolarisation (0)
•Early repolarisation (1); Plateau (2);
• Action potential duration (3,4; KATP?)

54
Q

What occurs at the neuromuscular junction at AP transmission?

A

Motor nerve impulse open synaptic voltage-gated Ca2+ channels
• Increased [Ca2+]i promotes synaptic vesicles migration to pre-synaptic membrane
•ACh released into synaptic cleft
➢Two ACh bind ACh-gated Na+ channel
➢Nicotinic cholinoreceptor (NAChR)

• increased [Na+]I depolarises muscle fibre

•T-tubule system propagates action potential
•Release of sarcoplasmic reticulum (SR) Ca2+
•Signal terminated by AChE
➢EPP terminated
➢Ca2+ returns to SR
➢Myasthenia Gravis – destroys NAChRs

55
Q

What occurs in the depolarising blockade of neuromuscular junction?

A

Prolonged activation of NAChR
➢Abolishes effector response

•Presence of nicotinic agonist inhibits post-synaptic membrane recovery
➢Can’t initiate muscle fibre action potential

•Skeletal muscle relaxes

•“depolarising blockade”

➢Suxamethonium (Sux; succinylcholine)
➢Anaesthetics Rapid Sequence Induction (RSI)
➢Sux not metabolised by AChE

56
Q

What is the membrane like?

A

Semi-permeable barrier
•Proteins facilitate transport and signalling functions
➢Carriers
➢Ion Channels
➢Receptors
•Maintains differential ion concentrations between intra-cellular and extra-cellular environments
➢Basis of membrane potential
●Influenced by acid:base balance and extra-cellular ion concentration

Phase 1 IMMS (5 decks)

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