Gene annotation for heart rhythm. 1. Control of heart rate 2. Action Potential 3. Ion channels and transporters 4. Arrhythmia 5.

Transcription

1 Gene annotation for heart rhythm 1. Control of heart rate 2. Action Potential 3. Ion channels and transporters 4. Arrhythmia 5. EC coupling

2 Control of heart rate

3 Autonomic regulation of heart function

4 Autonomic Regulation II Central integration of blood pressure and respiratory control Afferents via baroreceptors, chemoreceptors etc Integrated in brainstem centres

5 Effector arm Autonomic Regulation III Proteins involved in presynaptic vesicle release Proteins involved in signal transduction in the SA node

6 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 ΔR-R Frequency domain:- Potentially more revealing. HF=vagal\respiration, LF=sympathetic\BP control

7 What ionic mechanisms are responsible? Intrinsic rhythm set by SA node Modulation of pacemaker depolarisation β receptor activation Gs Adenylate cyclase Increased camp I f activation M2 receptor activation Gi\o Adenylate cyclase Decreased camp I f inhibition G βγ liberation I KAch activation

8 What is the intrinsic pacemaker? Spontaneous activity in the absence of innervation (intrinsic heart rate) Actually currently quite controversial Two hypotheses I f current is centrally important and\or Ca 2+ cycling

9 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 I f \HCN channels

10 Action potential

11 Cardiac Action Potential I

12 Anatomy Conduction system AP in heart regions

13 Cardiac action potential II I Kur Kv1.5 I KACh Kir3.1\3.4 I KATP SUR1\Kir6.1\Kir6.2 vs SUR2A\Kir6.2 Cx40 in atria. Cx43 in ventricle SK channels

14 Ion Channels and Transporters

15 What is happening at the molecular level? Ion channels predominantly control membrane excitability

16 Sodium channels SCN5A in the heart. Both beta subunits present.

17 Potassium channels

18 Lots of genes underlying K+ channels Current I to,f (I to1 ) Molecular composition α-subunit Kv4.3 and β-subunit KChiP2. I to,s (I to1 ) α-subunit Kv1.4 and possibly β- subunits (Kvβ1.2, Kvβ1.3 and I Kur I Kr I Ks I K1 Kvβ2) α-subunit Kv1.5 and β-subunit Kvβ1.2. α-subunit Kv11.1 (HERG) and probably β-subunit KCNE2. α subunit Kv7.1 (KCNQ1) and β subunit KCNE1. Kir2.1 and perhaps Kir2.2 and Kir2.3. Channel structure Function Location Reference(s) Octameric complex of a tetramer of 6 TMD α- subunits and 4 β subunits. A tetramer of 6 TMD α subunits may coassemble with 4 β-subunits. I KACh Kir3.1 and Kir3.4. 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) I KATP (Ventricular) I KATP (Atrial) Provides the rapid component of the transient outward current that contributes to early rapid repolarization during Phase 1. 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. A tetramer of 6 TMD α subunits associates with 4 β-subunits to form an octameric complex. A tetramer of 6 TMD α-subunits and an unknown number of 1 TMD β-subunits. Tetramer of 6 TMD α-subunits assembles with probably two 1 TMD β-subunits. Tetramer of 2 TMD α subunits. Contributes to late repolarisation, late phase 3, and helps to set membrane potential. During late phase 3 and phase 4 activation of I KACh 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. Kir6.2 and SUR2A. Octameric complex formed by coassembly of 4 2 TMD pore subunits and 4 17 TMD SUR subunits. Kir6.2 and SUR1. (Kir6.1?) Octameric complex formed by coassembly of 4 2 TMD pore subunits and 4 17 TMD SUR subunits. 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. Atrial and Ventricular. Atrial and Ventricular. Atrial. Atrial and Ventricular. Atrial and Ventricular. Ventricular and Atrial Predominantly Atrial and nodal tissue expression. Ventricular. Atrial. [23], [24], (a), (b) [25], [26], (a), (c) [27], [28], (d), (e) (f), (g), (h), (i) [20], [21], [22], (h), (i) [30], [31], (j), (k), (l) [32], [33], (j), (m), (n), (o), (p) [10], (q), (r), (s) [9], [10], (q), (r), (s) Also SK channels and twin pore channels

19 K channels in Long QT Voltage-gated (6-TM) KCNE family Extracellular H5 N Extracellular Intracellular N C Intracellular C alpha beta current KCNQ1 (KvLQT1) KCNE1 (IsK) Iks HERG KCNE2 (MIRP1) Ikr

20 Na + \K + ATPase Member of the P type ATPase pumps α1, α2 and α3 subunits. β1 and β2 auxiliary subunits Electrogenic 3Na + for 2K + but transport rate ~4 four fold less than the Na channel (100 ions\second)

21 Arrhythmia

22 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

23 Electrocardiogram (ECG) The benchmark of clinical diagnosis is the ECG P wave= atrial depolarisation QRS= ventricular depolarisation T wave=ventricular repolarisation

24 Examples Atrial Fibrillation Ventricular Tachycardia

25 Repolarisation and K + currents

26 Excitation-contraction coupling

27 Cardiac excitation-contraction coupling

28 Calcium channels Gene = CACNAx for alpha subunits (CACNA1C = Ca v 1.2) Ca v 1 = L-type, Ca v 2 = N-, P\Q and R type and Ca v 3 = T type

29 Ryanodine receptor RyR2 in heart Calcium induced calcium release LTCC and RyR2 opposed in T- tubule Large tetrameric complex Protein interactions

30 Sodium\calcium exchanger Major mechanism for calcium extrusion from the heart Electrogenic 3 Na + for single Ca 2+ Passive coupled counter transport system NCX1 in the heart (3 isoforms in total) Also P type ATPase Ca 2+ pump present in heart which actively extrudes Ca 2+ (PMCA)

31 SERCA2a and phospholamban Major mechanism for calcium uptake into SR P-type ATPase that transports Ca 2+ actively driven by ATP hydrolysis Regulated by phospholamban