Molecular Determinants of Na+ and K+ Channel Regulation in Heart:

Ion Channels as Targets of Neurohormones and Drugs

Electrical System of the Heart

Ion Channels in Heart

-Adrenergic Stimulation Shortens AP Duration

[Noradrenaline] (M)10-9 10-8 10-7 10-6 10-5(Kass & Wiegers, J Physiol. 1982)

Nor

mal

ized

cha

nge

in I C

aN

orm

aliz

ed c

hang

e in

I Ks

Targeting Proteins

AKAPS

KCNE1KCNQ1

KCNQ1+KCNE1

200 pA/pF

KCNQ1

0.5 s

50 pA/pF

B

A

(Splawski et al, Circ102;1178-85, 2000)

The KCNQ1 Macromolecular Complex

-40 -20 0 20 40 60 800

50

100 control cAMPOA

IKs.

tail

(pA

/pF)

(mV)-40 -20 0 20 40 60 80

0

50

100

(pA/

pF)

(mV)

wtKCNQ1+KCNE1(E1)+yotiao(Y) LZm KCNQ1+E1+Y

LZ mutation ablates functional up regulation

State-Dependent Block

Na Channels as models of drug targets

Voltage-Gated Sodium Channels

Na Channel Stucture

Gating and S4 Segments

Molecular Determinants of Inactivation

Inherited Mutations and Cardiac Arrhythmias

Lessons from Rare Genetic Disorders

A1924T

Mutations of inactivation gate alter inactivation

Dins1795NH2

E1784K

D1790G

COOH

++++++++++++

++++++++++++

++++++++++++

++++++++++++

KPQIFM

I II III IV

h H 1 K P Q

-8 0 -4 0 4 0 8 0

-1 00

-5 0pA

m V

Clinical studies: linking sympathetic nerve stimulation to Long-Sydrome

(LQT-1)

Genotype-phenotype correlation in the long-QT syndrome: gene-specific triggers for life-threatening arrhythmias.

Schwartz PJ, et al. Circulation 2001 Jan 2;103(1):89-95. "LQT1 patients experienced the majority of their events (62%) during exercise, and only 3% occurred during rest/sleep. "

J Am Coll Cardiol 2001 Feb;37(2):562-8

A founder mutation of the potassium channel KCNQ1 in long QT syndrome: implications for estimation of disease prevalence and molecular diagnostics.Piippo K, Swan H, Pasternack M, Chapman H, Paavonen K, Viitasalo M, Toivonen L, Kontula K.

Department of Medicine, University of Helsinki, Finland.

-40 -20 0 20 40 60 800

50

100

(pA

/pF)

(mV)

G589D KCNQ1+E1+Y

Mutation G589D ablates channel regulation

Drugs Can Induce LQT