Gene annotation for heart
rhythm
1.
2.
3.
4.
5.
Control of heart rate
Action Potential
Ion channels and transporters
Arrhythmia
EC coupling
Control of heart rate
Autonomic regulation of heart function
Autonomic Regulation II
• Central integration of blood pressure and respiratory control
• Afferents via baroreceptors, chemoreceptors etc
• Integrated in brainstem centres
Autonomic Regulation III
Effector arm
Proteins involved in presynaptic
vesicle release
Proteins involved in signal
transduction in the SA node
Heart Rate Variability
• The heart beat is not quite regular subject to small variations
• e.g. sinus arrhythmia
• Indicative of health. Correlates inversely with outcome after
MI etc
• Time domain:– Tachograms, SD of R-R or DR-R
• Frequency domain:- Potentially more revealing.
• HF=vagal\respiration, LF=sympathetic\BP control
What ionic mechanisms are responsible?
• Intrinsic rhythm set by SA node
• Modulation of pacemaker depolarisation
 receptor
activation
M2 receptor
activation
Gs
Adenylate
cyclase
Increased
cAMP
Adenylate
cyclase
Decreased
cAMP
Gi\o
Gg
liberation
IKAch
activation
If
activation
If
inhibition
What is the intrinsic pacemaker?
• Spontaneous activity in the absence of innervation
(intrinsic heart rate)
• Actually currently quite controversial
• Two hypotheses – If current is centrally important and\or
Ca2+ cycling
If\HCN channels
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•
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•
•
Activated by hyperpolarisation
Cation but otherwise nonselective
Directly opened by cAMP
HCN1-4, mainly HCN4 in heart
Largely expressed in SA node
Ivabradine used for the treatment
of angina
Action potential
Cardiac Action Potential I
Conduction system
Anatomy
AP in heart regions
Cardiac action potential II
– Kv1.5
• IKACh – Kir3.1\3.4
• IKATP – SUR1\Kir6.1\Kir6.2 vs SUR2A\Kir6.2
• Cx40 in atria. Cx43 in ventricle
• SK channels
• IKur
Ion Channels and Transporters
What is happening at the
molecular level?
Ion channels predominantly control
membrane excitability
Sodium channels
SCN5A in the heart. Both beta subunits present.
Potassium channels
Lots of genes underlying K+ channels
Current
Molecular
composition
Channel structure
Function
Location
Reference(s)
Ito,f (Ito1)
-subunit Kv4.3 and -subunit
KChiP2.
Octameric complex of a tetramer of 6 TMD subunits and 4 subunits.
Provides the rapid component of the transient
outward current that contributes to early rapid
repolarization during Phase 1.
Atrial and Ventricular.
[23], [24], (a), (b)
Ito,s (Ito1)
-subunit Kv1.4 and possibly subunits (Kv1.2, Kv1.3 and
Kv2)
-subunit Kv1.5 and -subunit
Kv1.2.
-subunit Kv11.1 (HERG) and
probably -subunit KCNE2.
 subunit Kv7.1 (KCNQ1) and 
subunit KCNE1.
Kir2.1 and perhaps Kir2.2 and
Kir2.3.
Kir3.1 and Kir3.4.
A tetramer of 6 TMD subunits may
coassemble with 4 -subunits.
Atrial and Ventricular.
[25], [26], (a), (c)
Atrial.
[27], [28], (d), (e)
Atrial and Ventricular.
(f), (g), (h), (i)
Atrial and Ventricular.
[20], [21], [22], (h), (i)
Ventricular and Atrial
[30], [31], (j), (k), (l)
Predominantly Atrial
and nodal tissue
expression.
[32], [33], (j), (m), (n), (o), (p)
Kir6.2 and SUR2A.
Octameric complex formed by coassembly of 4
2 TMD pore subunits and 4 17 TMD SUR
subunits.
Octameric complex formed by coassembly of 4
2 TMD pore subunits and 4 17 TMD SUR
subunits.
Provides the slow component of the transient
outward current that contributes to early rapid
repolarization during Phase 1.
Plays an important role in early phase (1-2)
atrial repolarization.
Repolarisation, outward rectifier during Phase
2 and 3.
Repolarisation, outward rectifier during Phase
2 and 3.
Contributes to late repolarisation, late phase 3,
and helps to set membrane potential.
During late phase 3 and phase 4 activation of
IKACh by acetylcholine acts to hyperpolarise the
membrane potential, slow the firing rate of
pacemaker cells in the SA and AV nodes and
delays AV conduction.
During late phase 3 and phase 4 this channel
acts to link cellular metabolism and membrane
excitability.
During late phase 3 and phase 4 this channel
acts to link cellular metabolism and membrane
excitability.
Ventricular.
[10], (q), (r), (s)
Atrial.
[9] , [10], (q), (r), (s)
IKur
IKr
IKs
IK1
IKACh
IKATP
(Ventricular)
IKATP
(Atrial)
Kir6.2 and SUR1.
(Kir6.1?)
A tetramer of 6 TMD subunits associates
with 4 -subunits to form an octameric complex.
A tetramer of 6 TMD -subunits and an
unknown number of 1 TMD -subunits.
Tetramer of 6 TMD -subunits assembles with
probably two 1 TMD -subunits.
Tetramer of 2 TMD subunits.
Tetrameric complex of 2 Kir3.1 and 2 Kir3.4 2
TMD subunits. (During development channel
may be formed by a homotetramer of Kir3.4)
• Also SK channels and twin pore channels
K channels in Long QT
Voltage-gated (6-TM)
H5
Extracellular
N
Extracellular
Intracellular
Intracellular
N
alpha
KCNQ1
(KvLQT1)
HERG
KCNE family
C
C
beta
current
KCNE1 (IsK)
Iks
KCNE2 (MIRP1)
Ikr
Na+\K+ ATPase
• Member of the P type ATPase pumps
• 1, 2 and 3 subunits. 1 and 2
auxiliary subunits
• Electrogenic 3Na+ for 2K+ but transport
rate ~4 four fold less than the Na channel
(100 ions\second)
Arrhythmia
This carefully orchestrated
activity can go wrong
Classification of arrhythmia
• Site of origin e.g. atrial, nodal, ventricular
• Rate e.g. bradycardia, tachycardia
• Process\Substrate e.g. fibrillation, heart
block, ectopic etc
Electrocardiogram (ECG)
The benchmark of clinical diagnosis is the ECG
P wave= atrial depolarisation
QRS= ventricular depolarisation
T wave=ventricular repolarisation
Examples
Atrial Fibrillation
Ventricular Tachycardia
Repolarisation and K+ currents
Excitation-contraction
coupling
Cardiac excitation-contraction coupling
Calcium channels
• Gene = CACNAx for alpha subunits (CACNA1C = Cav1.2)
• Cav1 = L-type, Cav2 = N-, P\Q and R type and Cav3 = T type
Ryanodine receptor
• RyR2 in heart
• Calcium induced calcium release
• LTCC and RyR2 opposed in Ttubule
• Large tetrameric complex
• Protein interactions
Sodium\calcium exchanger
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Major mechanism for calcium extrusion from the heart
Electrogenic – 3 Na+ for single Ca2+
Passive coupled counter transport system
NCX1 in the heart (3 isoforms in total)
Also P type ATPase Ca2+ pump present in heart which actively
extrudes Ca2+ (PMCA)
SERCA2a and phospholamban
• Major mechanism for calcium uptake into SR
• P-type ATPase that transports Ca2+ actively driven by ATP
hydrolysis
• Regulated by phospholamban