Download - Ionchannels and channelopaties in the heart
![Page 1: Ionchannels and channelopaties in the heart](https://reader036.vdocument.in/reader036/viewer/2022062803/5681473c550346895db47b8a/html5/thumbnails/1.jpg)
Ionchannels and channelopaties in the heart
Viktória Szűts
![Page 2: Ionchannels and channelopaties in the heart](https://reader036.vdocument.in/reader036/viewer/2022062803/5681473c550346895db47b8a/html5/thumbnails/2.jpg)
Action of membrane transport protein
ATP-powered pump Ion chanels Transporters 101-103ions/s 107-108ions/s 102-104ions/s
![Page 3: Ionchannels and channelopaties in the heart](https://reader036.vdocument.in/reader036/viewer/2022062803/5681473c550346895db47b8a/html5/thumbnails/3.jpg)
![Page 4: Ionchannels and channelopaties in the heart](https://reader036.vdocument.in/reader036/viewer/2022062803/5681473c550346895db47b8a/html5/thumbnails/4.jpg)
• Cardiac K+ channels control the resting membrane potentials and the amplitude, duration, refractoriness and automaticity of action potentials. K+ channels share a similar structure, composed by four pore-forming α-subunits assembled as tetramers or dimers forming K+
selective pores and modulated by accessory subunits. The main K+channel pore forming protein is not translated from a single gene as Na+ and Ca+channels, but is made up of four separate subunits, which assembly with ß-subunits to form the functional channel More than 80 different K+ channels are expressed in the heart, display considerable diversity of native K+channels.
• Ca-independent transient outward potassium current (I to1) underlies by KCNA genes encoded Kv3.x and Kv4.x proteins.
• Delayed rectifier currents: the rapid (IKr) and slow (IKs) are encoded by different voltage-gated K+ channel genes. IKr is produced by the α-subunit ERG (KCNH2), in co-assemblance with the ß-subunit MiRP1 (KCNE2). IKs is produced by the α-subunit KvLQT1 (KCNQ) assembly with the accessories subunits of minK and MIPRs (KCNE1, KCNE2, KCNE3)
• Inward rectifier current (IK1) carried by Kir 2.1, Kir 2.2 and Kir 2.3 (KCNJ2, KCNJ12 and KCNJ4) channel proteins.
![Page 5: Ionchannels and channelopaties in the heart](https://reader036.vdocument.in/reader036/viewer/2022062803/5681473c550346895db47b8a/html5/thumbnails/5.jpg)
Nerbonne et al . Circ Res. 2001;89:944-956
Molecular composition of the cardiac K-ionchannelsSelectivity filter
![Page 6: Ionchannels and channelopaties in the heart](https://reader036.vdocument.in/reader036/viewer/2022062803/5681473c550346895db47b8a/html5/thumbnails/6.jpg)
Membrane topology of the Kv and Kir2.x K-ionchannels
H5 H5
Voltage gated K+channel Inward rectifier K+channel
Kv channel
CO2
CO2
CO2
![Page 7: Ionchannels and channelopaties in the heart](https://reader036.vdocument.in/reader036/viewer/2022062803/5681473c550346895db47b8a/html5/thumbnails/7.jpg)
Kv complex
NN
CC
KChAP PSD
MiRP
![Page 8: Ionchannels and channelopaties in the heart](https://reader036.vdocument.in/reader036/viewer/2022062803/5681473c550346895db47b8a/html5/thumbnails/8.jpg)
Gating movi
Ionchannels are open and close changing the permeability
![Page 9: Ionchannels and channelopaties in the heart](https://reader036.vdocument.in/reader036/viewer/2022062803/5681473c550346895db47b8a/html5/thumbnails/9.jpg)
Abott et al Neuropharm. 2004
Assembly of different ionchannel subunits
Intracellular
Extracellular
![Page 10: Ionchannels and channelopaties in the heart](https://reader036.vdocument.in/reader036/viewer/2022062803/5681473c550346895db47b8a/html5/thumbnails/10.jpg)
Molecular assembly of ion channels
Cavα Kvα Kir
![Page 11: Ionchannels and channelopaties in the heart](https://reader036.vdocument.in/reader036/viewer/2022062803/5681473c550346895db47b8a/html5/thumbnails/11.jpg)
Activation and Inactivation of The Sodium Channel
Sodium channels are characterized by voltage-dependent activation, rapid inactivation, and selective ion conductance. Depolarization of the cell membrane opens the ion pore allowing sodium to passively enter the cell down its concentration gradient . The increase in sodium conductance further depolarizes the membrane to near the sodium equilibrium potential. Inactivation of the sodium channel occurs within milliseconds, initiating a brief refractory period during which the membrane is not excitable. The mechanism of inactivation has been modeled as a "hinged lid" or "ball and chain", where the intracellular loop connecting domains III and IV of the a subunit closes the pore and prevents passage of sodium ions.
![Page 12: Ionchannels and channelopaties in the heart](https://reader036.vdocument.in/reader036/viewer/2022062803/5681473c550346895db47b8a/html5/thumbnails/12.jpg)
• Voltage-Gated Calcium Channels• Voltage-gated calcium channels are heteromultimers
composed of an α1 subunit and three auxiliary subunits, 2-δ, β and γ. The α1 subunit forms the ion pore and possesses gating functions and, in some cases, drug binding sites. Ten α1 subunits have been identified, which, in turn, are associated with the activities of the six classes of calcium channels. L-type channels have α1C (cardiac), α1D (neuronal/endocrine), α1S (skeletal muscle), and α1F (retinal) subunits; The α1 subunits each have four homologous domains (I-IV) that are composed of six transmembrane helices. The fourth transmembrane helix of each domain contains the voltage-sensing function. The four α1domains cluster in the membrane to form the ion pore. The β-subunit is localized intracellularly and is involved in the membrane trafficking of α1subunits. The γ-subunit is a glycoprotein having four transmembrane segments. The α2 subunit is a highly glycosylated extracellular protein that is attached to the membrane-spanning d-subunit by means of disulfide bonds. The α2-domain provides structural support required for channel stimulation, while the δ domain modulates the voltage-dependent activation and steady-state inactivation of the channel.
![Page 13: Ionchannels and channelopaties in the heart](https://reader036.vdocument.in/reader036/viewer/2022062803/5681473c550346895db47b8a/html5/thumbnails/13.jpg)
Abriel H. et al., Swiss Med Wkly 2004, 685-694. www.sm w. ch
Ionic currents and ion transporters responsible for cardiac action potential
![Page 14: Ionchannels and channelopaties in the heart](https://reader036.vdocument.in/reader036/viewer/2022062803/5681473c550346895db47b8a/html5/thumbnails/14.jpg)
• The expression and properties of these K+ channels are altered in cardiac diseases (ie. cardiac arrhythmia, Long QT syndrome, hypertrophyc cardiomyopathy, Andersen syndrome, heart failure). These K+ channels still require further investigation because they are involved in the basic normal heart rhythm, and may be altered in cardiac diseases.
![Page 15: Ionchannels and channelopaties in the heart](https://reader036.vdocument.in/reader036/viewer/2022062803/5681473c550346895db47b8a/html5/thumbnails/15.jpg)
Proposed cellular mechanism for the development of Torsade de pointes in the long QT syndrome
![Page 16: Ionchannels and channelopaties in the heart](https://reader036.vdocument.in/reader036/viewer/2022062803/5681473c550346895db47b8a/html5/thumbnails/16.jpg)
• Prolonged QT interval on ECG (reflects prolonged APD)• APD governed by a delicate balance between inward (Na+
or Ca+) and outward (K+) ionic current• Affecting the Na+ or Ca+ channel prolong APD via“gain-off-
function”mechanism, while mutation in genes encoding K+ channel by “loss-off-function” mechanism
![Page 17: Ionchannels and channelopaties in the heart](https://reader036.vdocument.in/reader036/viewer/2022062803/5681473c550346895db47b8a/html5/thumbnails/17.jpg)
Risk factors for developing Torsade de pointes
Abriel H. et al., Swiss Med Wkly 2004, 685-694.
Genetic variants (polymorphysm or mutations)
![Page 18: Ionchannels and channelopaties in the heart](https://reader036.vdocument.in/reader036/viewer/2022062803/5681473c550346895db47b8a/html5/thumbnails/18.jpg)
Ionic current, proteins and genes associated with inherited arrhythmias
Napolitano et al. Pharm. & ther. 2006,110:1-13
![Page 19: Ionchannels and channelopaties in the heart](https://reader036.vdocument.in/reader036/viewer/2022062803/5681473c550346895db47b8a/html5/thumbnails/19.jpg)
Congenital and aquired forms of long QT syndromes
Abriel H. et al., Swiss Med Wkly 2004, 685-694. www.sm w. ch
![Page 20: Ionchannels and channelopaties in the heart](https://reader036.vdocument.in/reader036/viewer/2022062803/5681473c550346895db47b8a/html5/thumbnails/20.jpg)
K+, Na+ channel LQT-associated genes and proteins
LQT3 Brugada Syndrome, Cardiac conduction defect, Sick sinus syndrome
SCN5AINa
LQT7 Andersen-Tawil Syndrome Kir2.1 (KCNJ2)Ik1
LQT8 Timothy Syndrome Cav1.2 (CACNA1c)ICaL
Kir6.2IkATP
Kir3.4IkAch
Progressziv familial heart Block1Kv1.7(KCNA7),Kv1.5Ikur
LQT2LQT6, FAF
HERG (KCNH2)MiRP1 (KCNE2)
IKr
LQT1, JLN1LQT5, JLN2
KvLQT1(KCNQ1)Mink (KCNE1)
IKs
LQTKv4.3ITo1
DiseaseGenesCurrent
AF
![Page 21: Ionchannels and channelopaties in the heart](https://reader036.vdocument.in/reader036/viewer/2022062803/5681473c550346895db47b8a/html5/thumbnails/21.jpg)
![Page 22: Ionchannels and channelopaties in the heart](https://reader036.vdocument.in/reader036/viewer/2022062803/5681473c550346895db47b8a/html5/thumbnails/22.jpg)
Gene mutations in LQT1 and LQT2
LQT1LQT2
HERGKCNH2
KvLQT1KCNQ1
![Page 23: Ionchannels and channelopaties in the heart](https://reader036.vdocument.in/reader036/viewer/2022062803/5681473c550346895db47b8a/html5/thumbnails/23.jpg)
![Page 24: Ionchannels and channelopaties in the heart](https://reader036.vdocument.in/reader036/viewer/2022062803/5681473c550346895db47b8a/html5/thumbnails/24.jpg)
Molecular structure and the membrane topology of the
HERG channel
Mutations in HERG channel
![Page 25: Ionchannels and channelopaties in the heart](https://reader036.vdocument.in/reader036/viewer/2022062803/5681473c550346895db47b8a/html5/thumbnails/25.jpg)
Atrial fibrillation (AF):
• Rapid shortening of the AERP• Functional changes of ion channel• Reduction of ICaL and gene expression of L-
type Ca channel• Increase in K+-ion channel activity of IkAch,
Ik1
• Reduction in Ito and Isus
• Reduced gene expression in Kv1.5, Kv4.3, Kir3.1, Kir3.4, Kir6.2
![Page 26: Ionchannels and channelopaties in the heart](https://reader036.vdocument.in/reader036/viewer/2022062803/5681473c550346895db47b8a/html5/thumbnails/26.jpg)
Pivotal role of Ser phosphorilation as a regulatory mechanism in Cav1.2 mode1/mode2 gating.
Timothy’s syndrome
![Page 27: Ionchannels and channelopaties in the heart](https://reader036.vdocument.in/reader036/viewer/2022062803/5681473c550346895db47b8a/html5/thumbnails/27.jpg)
ShortQT
HERG (KCNH2)Kir2.x (KCNJ2)
KvLQT1(KCNQ1)
IKr
IK1
IKs
Kv3.1, Kv3.4
DiseaseGenesCurrent
ICaCASQ2 (Calsequestrin2) CPVT
CPVT catecholamine-induced polymorphic ventricular tachycardia
RyR2 CPVT
β1-adrenoceptor (β1-AR)
β2-adrenoceptor (β2-AR)
Risk factor, modify disease orinfluence progression of disease
Risk factor, modify disease orinfluence progression of disease
AF
ICa
IkAch
![Page 28: Ionchannels and channelopaties in the heart](https://reader036.vdocument.in/reader036/viewer/2022062803/5681473c550346895db47b8a/html5/thumbnails/28.jpg)
Complexity of protein-protein interaction in cardiomyocytes
![Page 29: Ionchannels and channelopaties in the heart](https://reader036.vdocument.in/reader036/viewer/2022062803/5681473c550346895db47b8a/html5/thumbnails/29.jpg)
Missense mutation in calsequestrin2 (CASQ2)
Associated with autosomal recessive catecholamine-induced polymorphic ventricular tachycardia (CPVT)
SyncopeSeizures orSudden death
In response to Physical activity orEmotional stress
wild type
mutant
![Page 30: Ionchannels and channelopaties in the heart](https://reader036.vdocument.in/reader036/viewer/2022062803/5681473c550346895db47b8a/html5/thumbnails/30.jpg)
Kir2.1 ionchannel has an autosomal dominant mutation in Andersen-Tawil Syndrome
Cardiac arrhytmiasPeriodic paralysisDysmorphic bone structure(scoliosis,low-set ears, small chin, broad forehead
![Page 31: Ionchannels and channelopaties in the heart](https://reader036.vdocument.in/reader036/viewer/2022062803/5681473c550346895db47b8a/html5/thumbnails/31.jpg)
Facial and sceletal features
in Andersen-Tawil syndrome
![Page 32: Ionchannels and channelopaties in the heart](https://reader036.vdocument.in/reader036/viewer/2022062803/5681473c550346895db47b8a/html5/thumbnails/32.jpg)
Kir2.1 ion channel mutation
GIRK mutation
![Page 33: Ionchannels and channelopaties in the heart](https://reader036.vdocument.in/reader036/viewer/2022062803/5681473c550346895db47b8a/html5/thumbnails/33.jpg)
ANP role
![Page 34: Ionchannels and channelopaties in the heart](https://reader036.vdocument.in/reader036/viewer/2022062803/5681473c550346895db47b8a/html5/thumbnails/34.jpg)
• Gene-specific mutation study• Genexpression study• Microarray, qRT-PCR• Proteomica
![Page 35: Ionchannels and channelopaties in the heart](https://reader036.vdocument.in/reader036/viewer/2022062803/5681473c550346895db47b8a/html5/thumbnails/35.jpg)
kir2.x mRNA in dog & human
-0.002000000.000000000.002000000.004000000.00600000
0.008000000.010000000.012000000.01400000
Kir2.1 Kir2.2 Kir2.3 Kir2.4
HUMAN
DOG
Kir2.x analysisby RT-PCR
![Page 36: Ionchannels and channelopaties in the heart](https://reader036.vdocument.in/reader036/viewer/2022062803/5681473c550346895db47b8a/html5/thumbnails/36.jpg)
RV LV RA LA RV LV RA LADOG HUMAN
n=12 n= 6
0
1
2
3
4
5
6
HUMAN DOG
Rel
ativ
e am
ount
of K
v1.5
LV
LA
kDa7566
Expression of Kv1.5 protein in human and dog
![Page 37: Ionchannels and channelopaties in the heart](https://reader036.vdocument.in/reader036/viewer/2022062803/5681473c550346895db47b8a/html5/thumbnails/37.jpg)
Co-localization of Kv2 auxillary subunit with Kv1.5 in dog left ventricular myocytes
100
Kv1.5-FITCKv2-Texas red
Kv1.5-FITC Kv2-Texas red
![Page 38: Ionchannels and channelopaties in the heart](https://reader036.vdocument.in/reader036/viewer/2022062803/5681473c550346895db47b8a/html5/thumbnails/38.jpg)