Ion Channels as Diverse Protein Complexes

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Ion Channels as Diverse Protein Complexes
William A. Coetzee wac3_at_nyu.edu Tel [phone]
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Inward Rectifier K Channels
Inward rectifier K channels

• The classical inward rectifier (IK1)
• G protein-activated K channels (IK,Ach IK,Ado)
• ATP-sensitive K channels (IK,ATP)
• Na-activated K channels

Setting the resting potential and automaticity.
Also responsible for repolarization of the action
potential and refractoriness (consequences for
contractility and arrhythmias)
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Inward Rectifier K ChannelsPharmacology

• Classical inward rectifiers
• Ba2, Cs
• G protein-activated K channels
• Acetylcholine, adenosine (mainly in atria)
• ATP-sensitive K channels
• Blocked by glibenclamide
• Opened by pinacidil, cromakalim, nicorandil

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Mechanism of Insulin Release

• Fasting state
• Low cytosolic glucose
• KATP channels are unblocked
• High K conductance
• Negative resting potential

b-cell
K
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Mechanism of Insulin Release

• After a meal
• Glucose taken up
• Glycolysis
• KATP channels blocked
• Depolarization
• Ca2 influx
• Secretory insulin release stimulated

Glucose
Insulin
ATP
Ca2
Depolarization
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K Channel Principal and Auxiliary Subunits
Voltage-gated K channels Ca2-activated K
channels
Leak K channels
Inward Rectifier K channels
6 TMD
4 TMD
2 TMD
KCR1
minK MiRPs
KCNK1 KCNK9 KCNK2 KCNK10 KCNK3 KCNK12 KCNK4 KCNK13
KCNK5 KCNK15 KCNK6 KCNK16 KCNK7 KCNK17
SUR
Kvb KChAP KChIPs NCS1
Kir
SUR1
SUR2
ABCC8
eag
KCNQ
SK
slo
Kv
Kir1
Kir2
Kir3
Kir4
Kir5
Kir6
Kir7
eag
erg
elk
Kir6.2
Kir6.1
Kv1
Kv2
Kv3
Kv4
Kv5
Kv6
Kv8
Kv9
KCNJ11
Coetzee, 2001
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Molecular Structure of KATP Channels
SUR regulatory subunits
Kir6 Subunits
Kir6.1 KCNJ8 Kir6.2 KCNJ11
SUR1 ABCC8 SUR2 ABCC9
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Combinations of Kir6/SUR subunits
(when expressed in heterologous expression
systems)
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Inward Rectifier K ChannelsGenetic Disorders
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The KCNJ11 gene
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SNPs

• Single nucleotide polymorphisms (SNPs) are common
  DNA sequence variations among individuals.
• Single base differences between human genomes
  underlie differences in susceptibility to, or
  protection from, a host of diseases..
• They offer great promise to significantly advance
  our ability to understand and treat human
  disease.

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Hypothetical Exam Question

• Discuss the molecular structure of the cardiac
  KATP channel. How does genetic variation KATP
  channel subunit genes help us to understand
  pathophysiological states?
• Frances M. Ashcroft. Ion Channels and Disease.
  Academic Press, 2000
• Seino S. ATP-sensitive potassium channels a
  model of heteromultimeric potassium
  channel/receptor assemblies. Annu Rev Physiol
  199961337-62