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Arrhythmogenic Coupling between
Na+-Ca2+ Exchanger and IP3 Receptor in
 Rat Pulmonary Vein Cardiomyocytes

 (ラット肺静脈心筋における Na+-
Ca2+ 交換体と IP3 受容体の共役による
        不整脈生成)

             岡本 洋介
http://lifesciencedb.jp/bp3d/
http://lifesciencedb.jp/bp3d/
http://lifesciencedb.jp/bp3d/
http://lifesciencedb.jp/bp3d/
http://lifesciencedb.jp/bp3d/
http://lifesciencedb.jp/bp3d/
http://lifesciencedb.jp/bp3d/
http://lifesciencedb.jp/bp3d/
http://lifesciencedb.jp/bp3d/
http://lifesciencedb.jp/bp3d/
http://lifesciencedb.jp/bp3d/
http://lifesciencedb.jp/bp3d/
http://lifesciencedb.jp/bp3d/
http://lifesciencedb.jp/bp3d/
4 μm
        4 μm                 4 μm




40 μm




                      2 μm                 2 μm
                                    2 μm
LA
     肺静脈心筋の形態的特徴

                 LA
            30

            20                                           PV
                                          50 µm
            10
Cells (%)




            0
                 PV
            30

            20
                                                         Ventricular Myocyte
            10

            0
                      1000     3000               5000
                             Area (µm2)


                                                                           20 µm
肺静脈心筋の電気生理学的特徴
A             B                                                                          C

    LA               LA                                             PV                       LA                            PV




                                                                                  10 pA/pF




                                                                                                               10 pA/pF
                                                                         100 ms                                           200 ms
             -60 -40 -20     mV 20        40              1.0
                                                          0.8
    PV                                                                                                                                   2
                                               Availability
                         -2
                              pA/pF




                                                          0.6
                     *   -4                               0.4
                                                                                              -120-100        -60 -40 -20
                                                                                                              mV                         -2
                                      *                                                                                                  -4




                                                                                                                                pA/pF
                         -6                               0.2
                         *                                                                                *
             20 mV




                                 *                                                                                                       -6
                                                          0.0
                                                                -60 -40 -20 0 20 40                                                      -8
         50 ms
                           * *
                         -10 *                                         mV                             *                                 -10
                                                                                                                                        -12
                                                                                                  *
Nicolas Doisne et al.
Am J Physiol Heart Circ Physiol (2009) 297:102-108.
肺静脈心筋のノルエピネフリン誘発自動
         能
            NE 10 μM
    A




                                                            40 mV
                                                    1 min
        NE 10μM               NE 10μM




                                                D




                                                             40mV
                                                    1 min
B                         C




                                                                    50 pA/pF
                                Voltage Clamp
                                    -50 mV




                                                                    40 mV
                  20 mV




             50 ms                                          1s
NE 10µM
A




                                         20 mV
                                 2 min

B                 NE 10µM
    Vm (mV)




                40

                -40

                0.3
    F405/F480




                0.2
                                1S
Vm (mV)
                      -60   -40   -20          0                  20   40

一過性内向き電流の                                -20
 電流 - 電圧関係                               -40

                                         -60




                                                   Current (pA)
 Na+/Ca2+ Exchanger                      -80

                                        -100

                                        -120




                                                                            100 pA
                                                                            40 mV
                                                                       2S
自動能停止後の持続的な Ca2+ 放出

NE 10µM
  SEA 0400 10μM




                        10 S
自動能に対する α1, β1 遮断薬の効果
NE 10µM
    Prazosin 1μM




    Atenolol 5 μM   1 min




                            40 mV
                    30 S
α1 シグナル伝達経路
NE 10 µmol/L

     U73122 1 µM




                                         40 mV
                                 30 S
      2-APB 2 µM




                                         40 mV
                                 30 S
  Calphostin C 1 µM




                                          40 mV
                                 2 min
Na+/Ca2+ 交換体と IP3 受容体の共局在
                                        Fluorescence intensity
                     103
                        4                               NCX
                        3                IP3R
                        2
                        1
                        0
                            0   1   2     3     4   5    6    7   8   9   10
                                                                          μm


                     x105
                        8
                        4
                                        AutoCorrelation: NCX
                        0
                       -2
NCX1                   -4
                            0   1   2     3   4     5    6    7   8   9   10
                                                                          μm
                     x104
                       20           AutoCorrelation: IP3R
                       10
                        0
                      -10
IP3R2                       0   1   2     3   4     5    6    7   8   9   10
                                                                          μm

                     x105       CrossCorrelation: NCX vs IP3R
                       10
                       0
                      -10

Merge                 -20
                            0   1   2     3   4     5    6    7   8   9   10
                                                                          μm
             10 µm
まとめ
形態的特徴 
 ・・・ NCX と IP3R が密に共局在した豊富な T 管
電気生理学的特徴 
 ・・・ ICaL, IK1 の電流密度が小さい
カテコラミン刺激伝達経路 
 ・・・ α1, β1 刺激依存性

α1 刺激による InsP3R からの
Ca2+ 放出が NCX と共役して脱分
極を促し、 β1 刺激によって活性化
されていた Ca2+ 動態と共に
Ca2+ サイクルを作り出す。

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学位審査

Editor's Notes

  1. There waw little change on the membane resistance (n = 3)