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Viktória Sz ű ts. Ionchannels and channelopaties in the heart. Action of membrane transport protein. ATP-powered pump Ion chanels Transporters 10 1 -10 3 ions/s 10 7 -10 8 ions/s 10 2 -10 4 ions/s.

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slide2
Action of membrane transport protein

ATP-powered pumpIon chanels Transporters

101-103ions/s 107-108ions/s 102-104ions/s

slide4
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)underliesby KCNAgenes 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).IKsis 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.
slide5
Molecular composition of the cardiac K-ionchannels

Selectivity filter

Nerbonne et al . Circ Res. 2001;89:944-956

membrane topology of the kv and kir2 x k ionchannels
Membrane topology of the Kv and Kir2.x K-ionchannels

Voltage gated K+channel Inward rectifier K+channel

Kv channel

CO2

CO2

CO2

H5

H5

kv complex
MiRP

N

N

C

C

KChAP

PSD

Kv complex
slide9
Assembly of different ionchannel subunits

Extracellular

Intracellular

Abott et al Neuropharm. 2004

slide11
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.

slide12
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.
abriel h et al swiss med wkly 2004 685 694 www sm w ch
Abriel H. et al., Swiss Med Wkly 2004, 685-694. www.sm w. ch

Ionic currents and ion transporters responsible

for cardiac action potential

slide14
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.
slide16
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
risk factors for developing torsade de pointes
Risk factors for developing Torsade de pointes

Genetic variants (polymorphysm or mutations)

Abriel H. et al., Swiss Med Wkly 2004, 685-694.

slide18
Ionic current, proteins and genes associated with

inherited arrhythmias

Napolitano et al. Pharm. & ther. 2006,110:1-13

congenital and aquired forms of long qt syndromes
Congenital and aquired forms of long QT syndromes

Abriel H. et al., Swiss Med Wkly 2004, 685-694. www.sm w. ch

k na channel lqt associated genes and proteins
Current

Genes

Disease

ITo1

Kv4.3

LQT

IKs

KvLQT1(KCNQ1)

Mink (KCNE1)

LQT1, JLN1

LQT5, JLN2

IKr

HERG (KCNH2)

MiRP1 (KCNE2)

LQT2

LQT6, FAF

INa

SCN5A

LQT3 Brugada Syndrome, Cardiac conduction defect, Sick sinus syndrome

Ik1

Kir2.1 (KCNJ2)

LQT7 Andersen-Tawil Syndrome

Ikur

Kv1.7(KCNA7),Kv1.5

Progressziv familial heart Block1

IkAch

Kir3.4

IkATP

Kir6.2

ICaL

Cav1.2 (CACNA1c)

LQT8 Timothy Syndrome

K+, Na+ channel LQT-associated genes and proteins

AF

gene mutations in lqt1 and lqt2
Gene mutations in LQT1 and LQT2

HERG

KCNH2

KvLQT1

KCNQ1

LQT2

LQT1

slide25
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
slide26
Pivotal role of Ser phosphorilation as a regulatory mechanism in Cav1.2 mode1/mode2 gating. Timothy’s syndrome
slide27
Current

Genes

Disease

IKr

IK1

IKs

HERG (KCNH2)

Kir2.x (KCNJ2) KvLQT1(KCNQ1)

ShortQT

Kv3.1, Kv3.4

CPVTcatecholamine-induced

polymorphic ventricular tachycardia

CASQ2(Calsequestrin2)

ICa

CPVT

ICa

CPVT

RyR2

Risk factor, modify disease or

influence progression of disease

β1-adrenoceptor (β1-AR)

Risk factor, modify disease or

influence progression of disease

β2-adrenoceptor (β2-AR)

IkAch

AF

slide29
Missense mutation in calsequestrin2 (CASQ2)

wild type

Syncope

Seizures or

Sudden death

In response to

Physical activity or

Emotional stress

mutant

Associated with autosomal recessive catecholamine-

induced polymorphic ventricular tachycardia (CPVT)

kir2 1 ionchannel has an autosomal dominant mutation in andersen tawil syndrome
Kir2.1 ionchannel has an autosomal dominant mutation in Andersen-Tawil Syndrome

Cardiac arrhytmias

Periodic paralysis

Dysmorphic bone structure(scoliosis,

low-set ears, small chin, broad forehead

slide34
Gene-specific mutation study
  • Genexpression study
  • Microarray, qRT-PCR
  • Proteomica
slide36
Expression of Kv1.5 protein in human and dog

kDa

75

66

RV LV RA LA RV LV RA LA

DOG HUMAN

n=12

n= 6

co localization of kv 2 auxillary subunit with kv1 5 in dog left ventricular myocytes
100 mCo-localization of Kv2 auxillary subunit with Kv1.5 in dog left ventricular myocytes

Kv1.5-FITC

Kv2-Texas red

Kv1.5-FITC

Kv2-Texas red

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