THE ACTION POTENTIAL

Objective:

Understand the Long QT syndrome and repolarization of membrane potential

-80 mV30 ms

Ventricular myocyte Squid axon

40 mV

Inwardly rectifying K current

Little current during the plateau of ventricular AP.

rabbit ventricular myocy

Shimoni et al, 1992

human atrial myocyt

Sakakibara et al, 19

Circulation Research

rabbit ventricular myocy

Shimoni et al, 1992

0

2

3

1

4

2 = IKr

3 = IKs

Temperature-sensitive mutations in Drosophila

melanogaster.

DT Suzuki

Science 170, 695-706, 1970

University of British Columbia

“Ether-a-go-go

eag

A distinct potassium channel polypeptide encoded

by the Drosophila eag locus.

Warmke, J., R. Drysdale and B. Ganetzky

Science 252, 1560-2, 1991

A family of potassium channel genes related to eag i

Drosophila and mammals.

Warmke, J. W. and B. Ganetzky.

PNAS, 91, 3438-42, 1994

HERG, a human inward rectifier in the voltage-gated

potassium channel family.

Trudeau, MC., JW. Warmke, B. Ganetzky & GA Roberts

Science 269, 92-95, 1995.

cDNA Channel

dofetilide/E-4031 block

0

2

3

1

4

2 = HERG = IKr

Long QT syndrome - QT > 0.5s

A boy with congenital Long QT syndro

that becomes “torsades de pointes”.

Q T

QT interval > 0.6 s

A molecular basis for cardiac arrhythmia: HERG mutatio

cause long QT syndrome.

Curran ME, Splawski I, Timothy KW, Vincent GM,

Green ED, Keating MT

Cell 80, 795-803, 1995

A mechanistic link between an inherited and an acquired

cardiac arrhythmia: HERG encodes the IKr potassium ch

Sanguinetti MC, Jiang C, Curran ME, Keating MT

Cell 81, 299-307, 1995

Action Potentials in Myocardium

Superior

Vena CavaSA Node

Atrium

AV Node

Purkinje

Tricuspid Valve

Mitral Valve

Ventricle

ECGP

PR QRS

Q

R

S

T

COOH

NH2

S1 S2 S3 S5 S6

HERG Long QT mutations

G628S

V822M

T474I

HERG in Chinese hamster ovary cells (CH

-80 to +60 mV

10 mV steps

T474I

CHO cells

Currently recognized LQTS disease genes

Disease Gene Chromosome Ion channel

LQT 1 KVLQT1a 11p 15.5 potassium

LQT 2 HERG 7q35-36 potassium

LQT 3 SCN 5A 3q21-24 sodium

LQT 4 ankyrin B 4q25-27 not a channel

LQT 5 Min K 21 potassium

Others……

HERG

S26I

F29L

N33T

C44F

G47V

G53R

R56Q

E58K

C64Y

T65P

C66G

H70R

P72Q

S1-S5

I400N

L413P

S428L

S436M

E444D

P451L

N470D

T474I

A490T

Y493C

D501N

R531Q

R534C

L552S

A558P

L559H

A561T

A561V

L564P

W568C

Y569H

G572R

G572C

E575G

R582C

G584S

W585C

N588D

I593R

I593G

P596L

G601S

G604S

D609N

Y611H

V612L

T613M

A614V

L615V

S621N

V625E

G626S

G626V

F627L

G628S

N629D

N629S

N629K

V630L

V630A

S631A

P632S

N633S

E637K

K638E

F640L

G643S

M645L

M645V

R752Q

R752W

C-te

R784

F805

F805

S818

V822

R823

R835

N861

P917

R922

S960

S5/Pore/S6

A78P

L86R

L87P

I96T

Y99S

K101E

P114S

M124T

R176W

R312C

P334L

P347S

N-term

Mutations