Ion Transport: Ion Channels
FACTORS DETERMINING TRANSPORT THROUGH ION CHANNELS
- Selectivity
- Conductance
- Rapid/ high: non-selective
- Slow/ low: highly-selective
- Gating
- Coordination of ion channel activity and cell function
ION CHANNELS IN EPITHELIAL CELLS
- Epithelial cells
- An interphase
- Polarised
- Apical (luminal)
- Basolateral (interstitial)
- Epithelial sodium channel
- ENaC
- Apical membrane
- Absorptive epithelia
- Alpha, beta, gamma subunits
- Cytoplasm, cell membrane, large extracellular loop, cytoplasm
- Na conducting pore
- Reabsorption of Na. Urine into interstitium. Down chemical gradient. Na pump in basolateral membrane.
- Hormonal control
- Aldosterone: Na retaining. Na reabsorption. K excretion.
- ANP: Natriuresis. Auppress ENaC.
- Liddle's syndrome
- Rare
- Autosomal dominant
- Hypertension
- Mutation beta gamma
- Pull Na out of apical membrane to cytoplasm
- Reducing ENaC activity
- Stucked channel
- Increases Na reabsorption
- Na overload. Hypertension. Suppression renin-aldosterone system. Hypokalaemia.
- Pseudohypoaldosteronism type 1
- Opposite to Liddle
- Didruption of pore-forming region
- Loss ENaC activity. Salt wasting. Potassium retention.
- Hypotension. Activation renin-aldosterone. Hyperkalaemia.
- Cystic fibrosis transmembrane conductance regulators
- Large continuous protein
- 2 repeating structures
- Each cross membrane 6x
- In epithelial cells . airways, duct of pancreas, sweat glands
- Functions
- Cl function
- Regulators of other ion transporter.
- Cystic fibrosis
- In the airway
- CFTR mutations
- Decreased Cl secretion
- Increased absorption Na
- Fluid thick & viscous, blocking bronchi, bronchioles. Bronchoectasis. Recurrent lung infections esp pseudomonas
- Die prematurely from respiratory failure
- In the pancreatic duct
- Secretion Cl and HCO3, water
- Failure of secretion
- Viscous
- Block ducts. Auto digestion. Pancreatic destruction.
- CF features: pancreatic insuff, malab. weifgt loss, failure to thrive
- Replace pancreatic enzymes, high calorie diet
- Insulin deficiency. diabetes mellitus
- In the sweat duct
- Cl reabsorption in sweats
- Unable to conserve Cl. High cl conc in sweat. Sweat test.
- Vulnerable to dehydration. Not able to reduce Cl, Na, H2O lost in sweat
ION CHANNELS IN NON-EPITHELIAL CELLS
- Muscle, nerve cells
- Ion channels regulate pass of ions
- Transmembrane potential difference
- Signal between cells. Alter intracellular calcium
- Cell membrane potential
- Ohms's law
- Potential difference
- Proportional to the current (number of ions moving across the membrane)
- Ion movement depends on
- Type
- Electrical and chemical gradient
- Nernst potential
- Resting cell potential
- K channels
- intracellular K 140, extracellular K 4
- K moves out
- Nernst potential for K 90mV
- Potential different is electrically negative (inside negative with respect to outside)
- Changes in membrane potential
- Cell membrane potential: negative inside
- Hyperpolarisation
- Inside becomes more negative
- Cations efflux
- Anion influx
- Depolarisation
- Inside more positive
- Anions efflux
- Cation influx
- Voltage gated sodium channels
- Alpha subunit
- 1 or more beta subunits
- Rapid changes in membrane potential
- Action potentials
- Resting
- Depolarisation
- Rapid channel opening
- Na influx (Inside 140, outside 10)
- Na influx depolarises
- Rapid inactivation of Na
- Na/K-ATPase
- Resting state restored by K channels
- Na channels
- Open
- Inactivated
- Cannot be reopen for a period of time
- Allows excitable cells to hyperpolarise before next action potential starts
- Closed
- Hyperpolarisation is complete
- Skeletal muscle cells
- Voltage-gated Na
- Activation
- Depolarisation
- Increase intracellular Ca
- Muscle contraction
- Inactivation & closure
- Hyperpolarisation
- Fall in intracellular Ca
- Muscle relaxation
- Mutations of alpha subunit
- No inactivation
- Persistent inward Na
- Hyperexcitability of skeletal muscle
- Myotonia
- Syndrome of impaired muscle relaxation
- Difficulty opening the hand after clenching a fist or opening the eyes after shutting them tightly.
- Paralysis
- Action potential cannot be generated
- Syndrome of hyperkalaemic periodic paralysis
- Intermittent attack of muscle weaknesss
- Spontaneously
- Precipitated by exercise, stress, K rich food.
- Cardiac mucle cells
- Action potential
- Opening NA channles
- Na influx
- Rapid depolarisation
- Na quickly inactivated
- Depolarisation maintained by Ca influx (plateau phase)
- Hyperpolarisation by K efflux
- Long QT syndrome
- Mutations
- Slow Na inactivation
- persistent Na influx
- Delay hyperpolarisation
- Prolong action potential
- Increase QT interval in ECG
- Torsades de pointes
- Sudden dysrhythmias in Long QT syndrome
- Sudden death
- Unknown mechanisms
- Mutant Na channels
- Failed to inactivated
- Reipen during prolonged hyperpolarisation
- Early after depolarisations
- Additional action potentials at multiple loci
- Nerve cells
- Familial epilepsy
- Mutation beta1 subunit
- Rate of activation
- Speed of recovery from inactivation
- Neuronal hyperexcitability and seizures.
- Drugs targeting voltage-gated Na channels
- Membrane stabilisers in dysrhythmias and epilepsy
- Restrict Na influx
- Slow cell depolarisation
- Limit cel responsiveness to excitation
- Class 1 antiarrhythmics
- Quinidine, disopyramide, lidocaine, flecainide
- Antiepileptics
- Phenytoin and carbamazepine
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