Session 3 ILOs - Transporters, Ion Channels & Pores 2-3

Question 1

How do transport proteins contribute to membrane permeability?

Answer 1

Transport proteins in the cell membrane allow for selective passage of specific molecules from the external environment

Question 2

Where does the energy come from for membrane transport?

Answer 2

Primary transport is driven directly by the hydrolysis of ATP to ADP+Pi
EXAMPLE: Calcium ATPase uses the hydrolysis of ATP to drive calcium out of the cell against the calcium concentration gradient
Secondary Transport uses the dissipation of gradients formed from another ion/molecule to drive the transport of the key molecule

Question 3

Name 2 conditions which involve the dysregulation of an ion transporter (lung & gut)

Answer 3

Cystic fibrosis (lungs): the chloride transporter (CFTR) is mutated and so chloride no longer passes across and out of the cell and therefore water doesn't follow. This leads to a very thick mucus layer in hollow lumens
Diarrhoea (gut): cholera infection can activate protein kinase A which increases the activity of the CFTR chloride transporter and therefore excess Cl- leaves the cell and water follows. The excess water in the gut leads to the symptoms of diarrhoea.

Question 4

Outline the main physiological role of Sodium-potassium ATPase (Na+-K+-ATPase,The‘Napump’)

Answer 4

1. Forms the Na+ & K+ gradients which are necessary for electrical excitability
2. Drives secondary active transport

Question 5

Outline the main physiological role of Plasma membrane Ca2+ ATPase (PMCA)

Answer 5

Primary active transport
Moves Ca2+ out of the cell in exchange for H+, which uses hydrolysis of ATP as energy
Has a high affinity & low capacity = mop up/restore resting levels

Question 6

Outline the main physiological role of Sarcoplasmic reticulum ATPase (SERCA)

Answer 6

Primary active transport
Accumulates Ca2+ into the sarcoplasmic ER in exchange for H+, which uses hydrolysis of ATP as energy
Has a high affinity & low capacity = mop up/restore resting levels

Question 7

Outline the main physiological role of Sodium calcium exchanger (NCX)

Answer 7

Secondary active transport
Moves Ca2+ out of the cell in exchange for 3Na+, uses Na+ gradient set up by the Na/K ATPase
Has a low affinity & high capacity = removes MOST of the calcium from the cell
(can flip in ischaemia & reverses = pathological)

Question 8

Outline the main physiological role of Sodium hydrogen exchanger (NHE)

Answer 8

Extrudes H+ out of the cell in exchange for Na+ (uses Na+ gradient) and prevents the cell from becoming too acidic e.g. during high metabolism

Question 9

Outline the main physiological role of Anion Exchange (AE)

Answer 9

Extrudes HCO3- out of the cell in exchange for Cl- (uses Cl- gradient across the membrane) and prevents the cell from becoming too alkalisation e.g. during high metabolism

Question 10

Outline how ion transport contributes to cellular Ca2+ handing

Answer 10

Ion transport helps to maintain low intracellular Ca2+ to prevent intracellular damage. 
PMCA: Extrudes Ca2+ in exchange for H+
SERCA: Transports Ca2+ into SER
NCX: Extrudes calcium in exchange for Na+
Mitochondria uniports (emergency - transports Ca2+ into mitochondria)

Question 11

Outline how ion transport contributes to cellular pH regulation

Answer 11

Cellular pH is controlled by acid extruders and base extruders
Acid extruders:
1. NHE (sodium hydrogen exchanger 1:1 ratio)
2. NBC (sodium bicarbonate cotransporter) - H+ & Cl- out, NA+ and HCO3- in
Base extruder:
1. Anion exchanger (Cl- and HCO3 exchanger, Cl- in and HCO3 out)

Question 12

Outline how ion transport contributes to cell volume regulation

Answer 12

Ion transport of osmotically active ions:
Na+, K+, Cl- or organic osmolites e.g. amino acids
If cell is swelling…extrude ions
If cell is shrinking…influx ions

Question 13

Outline how ion transport contributes to renal bicarbonate reabsorption

Answer 13

Bicarbonate reabsorption in the proximal tubule helps with pH control
See notes for diagram

Question 14

Outline how ion transport contributes to renal Na+ handling

Answer 14

Na+ reuptake in the kidney helps with hypertension

See notes for diagram

Question 15

Describe how organic anion transporters (OATs) mediate the cellular uptake of organic anions

Answer 15

OATs are mainly expressed in the proximal tubules where they mediate transport of mainly small hydrophilic organic anions into the cell, in exchange for decarboxylate ions (active process)

Question 16

Describe how renal OATs may affect attained plasma drug levels

Answer 16

If a drug is negatively charged, OATs may transport the drug from the blood and back out into the lumen to be excreted = reducing the therapeutic concentration in the blood

Question 17

Describe, in principle, how OATs may contribute to inter-organ and inter-organismal communication

Answer 17

Inter-organ: OATs can pick up signalling molecules that have been released by one tissue and take them up into a secondary tissue = allowing organs to communicate
Inter-organismal: OATs can put molecules into the faeces via the intestine

Question 18

Describe how organic cation transporters (OCTs) mediate the cellular uptake of organic cations

Answer 18

OCT transporters are driven by the negative membrane potential and transport positively charged molecules from the blood and into the cell (passive)

Question 19

Describe how renal OCTs may affect attained plasma drug levels

Answer 19

OCTs may transport positively charged drug molecules from the blood into the cell = reducing the therapeutic concentration in the blood

Question 20

Describe how OCTs may enhance cytotoxicity of anti-cancer drugs and result in nephrotoxicity in parallel

Answer 20

OCTs may transport anti-cancer drugs into the cell (if they are well suited for the OCT2 transporter). However the drug isn’t generally a good substrate for MATEs (Multidrug and toxin extrusion proteins) which take substances from the cell into the lumen to be removed, therefore the anti-cancer drug builds up in the cell which can lead to cell toxicity and death (ideal in cancer cells!!)
EXAMPLE: Cisplatin is an excellent substrate for OCT2