Download I Kr

Voltage-dependent K currents
(currents, channels, genes)
+50
-80
Transient outward
(Ito: Kv4.3: KCND3)
-70
6000
5000
4000
Delayed rectifier, ultrarapid
(IKur: Kv1.5: KCNA5)
3000
2000
1000
0
200
-1000
-2000
-3000
-4000
pA -5000
400
600
800
1000
1200
1400
ms
Delayed rectifier, rapid
(IKr: HERG: KCNH2)
-6000
Delayed rectifier, slow
(IKs: KvLQT1: KCNQ1)
Schematic representation of the three groups of
K+ channel principal subunits
KCNQ
important
in heart
Transient outward K current in ventricle
120
2.2
100
80
60
2.0
40
20
0
-20
1.8
0
50
100
150
200
250
ms
-40
-60
mV
1.6
-80
-100
1.4
1.2
1.0
0.8
0.6
0.4
0.2
nA
0.0
-0.2
0
50
100
150
200
250
ms
nA
outward rectifying
IV-curve
2.0
1.5
1.0
0.5
0.0
-100
-80
-60
-40
-20
0
20
40
60
80
100
mV
120
Contribution of Ito : Simulation study
Ventricle
mV
3.6
3.4
3.2
3.0
2.8
2.6
2.4
2.2
2.0
1.8
1.6
1.4
1.2
1.0
0.8
0.6
0.4
0.2
0.0
-0.2
Density 0.1
Density 1
Density 5
0
50
100
150
200
ms
80
Density 0.1
60
Phase 1 repolarization에 중요
Density 1
40
Density 5
20
0
-20
-40
-60
mV
-80
-100
0
50
100
150
200
Different Ito distribution is responsible for
regional difference of AP shape between Epi and Endo:
Spike and Dome in Epicardial AP
Block of Ito
Ito
4-AP:
K channel blocker,
more selective to Ito
- Prominent phase 1 notch in epicardial cells
- 2- 5 folds more Ito in Epi cells than in Endo cells
- Different response to Ito blockade
Transient outward current in cardiac pathology
• Decreased Ito and corresponding mRNA
expression of Kv4.2 and/or Kv4.3 in cardiac
hypertrophy.
• Ito 감소 --- AP duration 증가 --- Ca2+ influx 증가
--- activate calcineurin and transcription of
hypertrophy responsive genes
• Atrial fibrillation induces electrical remodeling --decrease Ito --- promote the perpetuation of AF
Sinoatrial node
cells
IKr contributes to repolarization in ventricle and atrium
C
Atrial cells
IKr blocker
Contribution of IKr : Simulation study
SA node
B Density : 1
C Density : 1.5 -> control
D Density : 2
40
20
0
0
-20
-40
-60
-80
200
400
600
800
1000
Contribution of IKr : Simulation study
Ventricle
B Density : 0
C Density : 1
D Density : 10
60
40
20
0
0
-20
-40
-60
-80
-100
200
400
600
800
1000
Defect of HERG causes Long QT Syndrome
Defect of HERG by mutation (genetic) or
drugs (aquired)
Early AfterDepolarization
Prolongation of APD
Prolongation of QT interval in ECG
(LQT Syndrome)
Causes life-threatening Arrhythmias
** Long QT Syndrome: 심전도상 QT 분절이 길어져 있고 심실빈맥, 심실세동, 실신 (syncope),
급사 등을 유발하는 상염색체 우성 질환
IKur
• Repolarizing K current in atrium,
but not present in ventricle
• Blocked by low concentration
of 4-AP
• Atrial fibrillation induces
electrical remodeling
decrease IKur
triangular AP
promote the perpetuation of AF
Inward rectifiers
- Kir1.1-1.3: weak inward rectifier
- Kir2.1-2.4: strong inward rectifier (IK1 in heart)
- Kir3.1 + 3.4: GirK (acetylcholine-activated in heart, IK,Ach)
- Kir6.2: ATP-sensitive K channels
+ SUR1: pancreatic beta cell
+ SUR2A: heart and skeletal m.
+ SUR2B: vascular smooth m.
- Kir6.1: IK(NDP) ADP-activated K channels
+ SUR2B: vascular smooth m.
I-V relationships for K currents
I
Outward rectifying: Kv
Linear (leaky)
EK
EK
V
RMP
Peak
Inward rectifying
Weak:
KAch, KATP
Strong: IK1
V
I-V relationship of inward rectifier K current, IK1
-40 mV
0.5
-20 mV
0.0
0
200
400
600
800
1000
-0.5
-1.0
-1.5
-100 mV
-110 mV
-2.0
-120 mV
1) Inward rectification: Large conductance at RMP, but allow
little outward current at plateau
2) Conductance increase by increasing [K+]o (hyperkalemia)
Effect of external K concentration
(Normal Serum K+: 3.5 – 5 mM)
세포외 K
농도 증가
Depolarization
of RMP
Na channel의
availability 감소
1. 자극 threshold 증가
2. Upstroke dV/dt 감소
Conduction 느려짐
Contribution of IK1 : Simulation study
100
Ventricle
B
C
D
80
60
Density : 0
Density : 1
Density : 5
40
20
0
-20
0
200
-40
-60
-80
-100
SA node
B Density : 0
C Density : 0.03 -> control
D Density : 1
40
20
0
0
-20
-40
-60
-80
200
400
600
800
1000
Andersen syndrome
autosomal dominant channelopathy in Kir2.1(KCNJ2)
• Kir2.1 play a critical role in
excitable cells (muscle, heart,
neuron) and developmental
processes
• Symptoms:
- Ventricular arrhythmias and
prolongation of the QT interval on
the resting EKG
- Skeletal muscle dysfunction:
periodic paralysis is most common
- Distinctive physical features
affecting craniofacial features
(hypertelorism, micrognathia, lowset ears, and high arched or cleft
palate) and the trunk and limbs
(short stature, scoliosis, syndactyly,
and clinodactyly).
D172N
Ventricular AP
Ito
Upstroke
INa
Balance between
IK and ICa INa/Ca
and persistant INa
ICa
IK and IK1
RMP
IK1
IK
ICa
IK
Sinoatrial Node
Upstroke
Repolarization
ICa
IK
MDP
Pacemaker
Depolarization ? ? ?
Ib, IK, absence of IK1
IK decay, If , ICa, Ib
Frequency, slope of pacemaker depolarization: Ih, ICa
Frequency, MDP, slope of pacemaker depolarization : IKACh
Ih, ICa
Acetylcholine-activated K current
GIRK
acetylcholine
OUT
M2
IN
M2
bg
a bg
GTP K+
a
GDP
ACh
ACh
500 pA
a b
c
d
2 min
Electrical Activity에 관한 공부
1)
Generation and Conduction of Action Potential
2)
Generation of ECG:
- conduction of depolarization wave
- electrical heterogeneity of AP
3)
Ionic Basis of Action Potentials: How to understand the
generation of electrical signal (V) from the characteristics of ion
channels and currents (I): I vs V
4)
Abnormal electrical activity (Arrhythmias)
: abnormal automaticity // abnormal conduction
부정맥의 분류
- 발생부위에 따라: ventricular
atrial
AV junction
sinus
- Altered rhythm의 형태에 따라: bradycardia/tachycardia
flutter
fibrillation
- A-V Block: 1st / 2nd / 3rd degree
Cardiac Arrhythmia
Disturbance of :
1) Impulse propagation: Conduction block
Reentry
2) Impulse initiation: Altered sinus rhythm
Abnormal automaticity
(Ectopic focus)
Triggered activity
Abnormal automaticity
can occur anywhere in the heart,
membrane potential : –70 to –30 mV.
Mechanism:
decrease in outward K+ current
a reduced maximal depolarization (slow response type)
slow, inward Ca2+ channels because the Na+ channels responsible for the fast
response are deactivated at reduced membrane potentials
Clinical example: Purkinje cells in an ischemic region after myocardial infarct. Loss
of K+ and uptake of Na+ (Ca2+, H+ and water accumulate as well) within the
ischemic cell result in a reduced membrane potential which can lead to
automaticity.
Arrhythmias caused by abnormal automaticity will not be visible unless the rate of
the abnormal focus is greater than the dominant pacemaker.
Triggered activity
Early Afterdepolarization
Delayed Afterdepolarization
APD 증가
Ca channel reactivation
세포내 Ca overload
Na/Ca exchange current
Long Q-T Syndrome
 심전도상 QT 분절이 길어져 있
고 심실빈맥, 심실세동, 실신
(syncope), 급사 등을 유발하는
상염색체 우성 질환.
QT interval: APD
 최근의 분자생물학적 연구에서
이 증후군의 유전자 돌연변이 종
류가 밝혀지며 이들이 심근세포
의 이온 통로를 encode하는 유
전자임이 밝혀짐.
Long QT Syndrome (LQTS)
• LQT1 : loss of function mutation in the KCNQ1 (KvLQT1,
a subunit of IKs)
• LQT2: loss of function mutations in the KCNH2 (HERG,
a subunit of IKr)
• LQT3: gain of function mutations in the SCN5 (Nav5.1, INa)
• LQT4: Ankyrin B
• LQT5: loss of function mutations in the KCNE1 (minK, b
subunit of IKs)
• LQT-6: loss of function mutations in the KCNE2 (MiRP1,
b subunit of IKr)
후천성 LQT 증후군
 항히스타민제, 항생제 등에 의하여 발생
이들 약물들은 HERG 통로를 억제함이 밝혀지
고 있어서, 선천성 LQT 증후군 중의 한 형태
(LQT2)와 후천성 LQT 증후군의 생리학적인 기
전이 같음을 알게 되었다.
 신약개발시 HERG channel block 여부를 검사
하는 것이 필수적인 것으로 인식되고 있음.
Reentry: circulating excitation
1. Unidirectional block
2. Prolonged conduction time
3. Short refractory period
Conduction velocity 느려지고, refractory period 짧을수록
Arrhythmia 발생 쉬워짐
Short QT Syndrome (SQTS)
• SQT1 : gain of function mutation in the
KCNH2 (HERG, a subunit of IKr)
• SQT2: gain of function mutations in the
KCNQ1 (KvLQT1, a subunit of IKs)
• SQT3: gain of function mutations in the
KCNJ2 (Kir2.1, IK1)
Coronary circulation
Ischemic Heart Disease
관상동맥 막힘
Ischemia(허혈), Infarction(경색)
세포내 ATP 감소
KATP Channel의 활성화
활동전압 duration 짧아짐, K의 유출로 세포밖 K 농도 증가
수축 감소로 energy saving의 효과 (cardioprotective)
동시에 부정맥 발생 위험 증가 (arrhythmogenic)
Voltage-gated K+ channel
KATP channel
Kir6.2
SUR (sulfonylurea receptor)
Papazian (1999) Neuron 23: 7-10
ATP-Sensitive Potassium-Channel in pancreatic b-cell
•
•
•
•
•
play a central role in glucose-stimulated insulin secretion from pancreatic beta cells:
insulin secretion is initiated by closure of the channels and inhibited by their opening.
Sulfonylureas stimulate insulin secretion by closing K(ATP) channels
SUR truncation or Kir6.2 missense mutation: Familial persistent hyperinsulinemic
hypoglycemia of infancy
Activating Mutations in Kir6.2: Permanent Neonatal Diabetes
Targeted Overactivity: Profound Neonatal Diabetes
Differential response of Endo and Epi cells to ischemia
Epi cell의 KATP가 ATP감소에 more sensitive
Electrical heterogeneity induced by ischemia produces
ST elevation
Epicardial AP: Spike and Dome
mechanism inducing electrical heterogeneity
(Pinacidil, KATP channel opener)
slight shortening
of APD
heterogeneous effect on APD:
marked shortening (loss of dome)
or lengthening (delayed)
Phase 2 reentry
Lukas and Antzelevitch.
Cardiovasc Res 32: 593-603, 1996
Phase 2 reentry-initiated circus movement tachycardia
Effect of ischemia
Effect of KATP opener
-Loss of “Dome” in some part but not all causes re-entry
-Circus movement is produced when the size of the tissue is large enough
Reentry
Anatomic
Functional
Reflection
Leading circle vs. Spiral wave
Phase 2 reentry
Anisotropic