Pulmonary Vein, Arrhythmogenic Coupling

Arrhythmogenic Coupling between Na+-Ca2+ Exchanger and IP3 Receptor in

Rat Pulmonary Vein Cardiomyocyte

Yosuke Okamoto1, Makoto Takano2,

Kouiti Kawamura3, Takayoshi Ohba1,

Kyoichi Ono1.

1Department of Cell Physiology, Akita University Graduate School of Medicine2Department of Physiology, Kurume University School of Medicine, Kurume

3Department of Cellular and Organ Pathology, Akita University Graduate School of Medicine

Haïssaguerre M, Jais P et al.　N Engl J Med. (1998) 339: 695-666.

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40 μm

4 μm 4 μm

2 μm2 μm 2 μm

4 μm

Nicolas Doisne et al.Am J Physiol Heart Circ Physiol (2009) 297:102-108.

LA

PV

Ventricular Myocyte

Area (µm2)

Cel

ls (

%)

20 μm

LA

PV

500030001000

30

20

10

0

30

20

10

0

50 µm

A

-10

-6

-2

pA/p

F20 40-60

-4

-40 -20

20 m

V

50 ms

PV

LA

pA/pF

mV

-12

-10-8

-6-4-2

2

-120-100 -60 -40 -20

*

*

*

B

100 ms

LA PV

1.0

0.8

0.6

0.4

0.2

0.0-60-40 -20 0 20 40

mV

Ava

ilabi

lity

10 p

A/p

F

*

* **

*

*

C

200 ms

10 p

A/p

F

mV

LA PV

*

40 m

V

1 min

1 min

NE 10μM

40m

V

NE 10 μM

NE 10μM

A

D

B

50 ms 20 m

V

C

50 p

A/p

F40

mV

1 s

Voltage Clamp

-50 mV

40

-40Vm

(m

V)

0.2

0.3

F40

5/F

480

1 S

2 min

NE 10μM

20 m

V

A

B NE 10μM

100

pA40

mV

2 S

Vm (mV)

Cur

rent

(pA

)

-120

-100

-80

-60

-40

-20

-60 -40 -20 20 400I-V Relationship of Arrhythmogenic Inward CurrentsInduced by NE

Na+/Ca2+ Exchanger

40

-40

0.3

0.2

Vm

(m

V)

F40

5/F

480

10 S

SEA 0400 10μM

NE 10μM

Spontaneous Ca2+ releasing after Cessation of Automatic Action Potentials

The Effect of α1 and β1 Antagonists

Prazosin 1μM

1 minAtenolol 5 μM

30 S

40 m

V

NE 10μM

NE 10 μmol/L

Calphostin C 1 μM

40 m

V

U73122 1 μM

2-APB 2 μM

30 S 40 m

V

30 S 40 m

V

2 min

Cascade of α1 signal transduction

Co-localization of Na+/Ca2+ Exchangers and IP3 R

0 1 2 3 4 5 6 7 8 9 10

0 1 2 3 4 5 6 7 8 9 10

0 1 2 3 4 5 6 7 8 9 10

0

10

-10

-20

x105

0

20

-10

10

x104

04

-2-4

x105

8

0 1 2 3 4 5 6 7 8 9 10μm

μm

μm

μm

012

43

103

NCXIP3R

Fluorescence intensity

AutoCorrelation: NCX

CrossCorrelation: NCX vs IP3R

AutoCorrelation: IP3R

10 μm

NCX1

IP3R2

Merge

“Ca2+ release via the IP3R is activated by α1 stimulant, and the Ca2+ in

turn spin up the NCX, which is co-localized with the IP3R, producing

transient depolarization. β1-adrenergic action of NE reinforce CICR,

resulting in Ca2+ overload. The accumulated Ca2+ would be released

again via the IP3R. ”

Okamoto Y et al. J Mol Cell Cardiol. 2012 (in press)