Molecular diversity of ion channels

Question 1

Activation of voltage gated K+ channels

Answer 1

• arginine + lysine residues on 4th helix, function as voltage sensors
• depol of membrane - conformational change of sensors

Question 2

N-type inactivation, ball&chain mechanism of voltage gated K+ channels

Answer 2

• inactivation can be eliminated by enzymatic cleavage or artificial deletion of N-terminus
• inactivation of N-terminally truncated channels can be restored - exposure to isolated N-terminal peptide
• in some: B subunit provides ball&chain

Question 3

Kv1.1 votage gated K+ channel associated disease

Answer 3

location: CNS, PNS, dendrites, axon terminals
role: repol. after AP
mutations: ataxia, myokymia

Question 4

KCNQ1, HERG, voltage gated K+ channel associated disease

Answer 4

location: ventricular myocytes
role: repol. after AP
mutations: prolonged ventricular AP, ventricular fibrillation, sudden death

Question 5

KCNQ2/3 voltage gated K+ channel associated disease

Answer 5

location: neurons (hippocampus, symp. ggl.)
role: decreases excitability
mutatuin: benign familial neonatal epilepsy

Question 6

ATP sensitive K+ channels

Answer 6

• octamer: 4 poreforming K+ channel subunits + 4 sulfonylurea receptor subunits
• SUR: 3 TMDs, 2 i.c. NBDs
• ER retention signal ensures correct assembly of octamer
• has inward rectification
• ionic current outwards blocked by i.c. MG2+ + polyamines

Question 7

Kir 6.1 and SUR1

Answer 7

location: pancreatic B cell
role: increase ATP/ADP ratio - Katp channel shut - depol. - insulin secretion
mutations: persistent hyperinsulinaemic hypoglycemia
+ type 2 diabetes mellitus

Question 8

Kir 6.2 and SUR 2A

Answer 8

location: cardiac myocytes, skeletal m.
role: ischemia - AP duration decrease - contractility decrease

Question 9

Kir 6.1 and SUR 2B

Answer 9

location: vascular smooth m
role: decrease vascular tone
medical significance: hypertension - treated with cromakalin

Question 10

Voltage gated Cl- channels

Answer 10

• homodimer
• mutations:
  
  • in muscle: hyperactive muscle fibers
  • in kidney: hypercalciuria, salt wasting
    e. g. CFTR

Question 11

CFTR Cl- channel

Answer 11

• cystic fibrosis transmembrane conductance regulator
• ABC family
• 1 polypeptide chain
  
  • 2 TMDs
  • 2 ic NBDs
  • 1 regulatory domain : phosphorylated by PKA - activation - gating requires ic ATP - ATP drives gating by binding to NBDs - NBD2 head hydrolyzes ATP - closes
• active conformation: head-tail NBD1-NBD
• mediacal significance:
  
  • location: lungs, pancreatic duct cells, intestinal epith., sweat glands
  • mutation -> viscous mucus in lungs, pancreatic insufficiency etc.

Question 12

Activators and inhibitors of ATP-sensitive K+ channels

Answer 12

Activator:

• ADP
• K+ channel openers (e.g. diazoxide)

Inhibitors:

• ATP
• sulfonylureas (e.g. tolbutamide)

Question 13

Clc-0 Cl- channels

Answer 13

• double barreled shotgun with common lock: 2 independently gated pores, also common slow gate
• Cloning and biochemical characterization of Clc-0 Cl- channels purified from Torpedo electroplax:
  *molecular weight of the monomer is 90 kDt
• sedimentation velocity corresponds to 200 kDt
  ⇒ the active channel is a homodimer

Question 14

Clc-1

Answer 14

location: skeletal muscle
role: stabilizes resting membrane potential
mutations: unstable resting potential, hyperactive muscle fiber ⇒ myotonia