Channel Opa Thies

7/28/2019 Channel Opa Thies

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The Neurological Channelopathies


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Type Gene Channel Disease

Voltage

-gated

Na+ SCN4A subunit of NaV1.4 HyperK periodic paralysis

HypoK periodic paralysisParamyotonia congenita

K+ KCNJ2 subunit of Kir2.1 Andersens syndrome

KCNE3 Accessory subunit

MiRP2 (assembles with

KV3.4)

HypoK periodic paralysis

Ca2+ CACNA1S subunit of CaV1.1 HypoK periodic paralysisMalignant hyperthermia

RYR1 Ryanodine receptor

(sarcoplasmic channel)

Malignant hyperthermia

Central core disease

Cl- CLCN1 ClC1 Myotonia congenita

Ligand-

gated

Nicotinic

AChRs

CHRNA1 1 subunitCongenital myasthenic

syndromesCHRNB1 1 subunit

CHRND subunit

CHRNE subunit

1: Disorders of muscle


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2: Disorders of neurons


Voltage

-gated

Na+ SCN1A subunit of NaV1.1 GEFS+,SMEI

SCN2A subunit of NaV1.2 GEFS+

SCN1B 1 subunit

K+ KCNA1 subunit of Kv1.1 Episodic ataxia type 1

KCNQ2 M current BFNC

KCNQ3Ca2+ CACNA1A subunit of CaV2.1

(P/Q channel)

Familial hemiplegic migraine

Episodic ataxia type 2, SCA6

CACN1H subunit of CaV3.2(T-type channel)

Absence epilepsy

Cl- CLN2 ClC-2 Idiopathic generalised epilepsy

Ligand-

gated

Nicotinic

AChRs

CHRNA2 4 subunit AD nocturnal frontal lobe epilepsy

CHRNB4 2 subunit

GlycineR GLRA1 1 subunit Familial hyperekplexia

GABAAR GABRG2 2 subunit GEFS+

GABRA1 1 subunit Juvenile myoclonic epilepsy


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Gap-

junction

protein

GJB1 Connexin 32

(paranodal myelin)

X-linked Charcot-Marie-Tooth

disease

3: Disorders of glial cells


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Cooper & Jan 1999


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Voltage-gated channels


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Na+ channelopathies

Gene Channel Disease

Muscle SCN4A subunit of NaV1.4 Hyperkalaemic periodic paralysisHypokalaemic periodic paralysis

Paramyotonia congenita

Potassium-aggravated myotoniaMyotonia fluctuans

Myotonia permanens

etc

Neuronal SCN1A subunit of NaV1.1(somatic)

Generalised Epilepsy with Febrile

Seizures + (GEFS+),

Severe myoclonic epilepsy ofinfancy (SMEI)

SCN2A subunit of NaV1.2(axonal)

GEFS+

SCN1B 1 subunit


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Skeletal muscle Na+ channel NaV1.4


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Na+ channel activation, deactivation and inactivation


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Potassium-aggravated myotonia mutations affect single channel behaviour


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Most muscle Na+ channelopathies are:

dominantly inherited

associated with high serum [K+]

caused by impaired fast inactivation (mutations around III-IV linker, or

cytoplasmic receptor)

Mild impairment of fast inactivation myotonia

Severe impairment Na+ channels enter slow inactivated state

Hypokalaemic periodic paralysis can result from loss of function of Na+ channel

(mutations cluster in S4 voltage sensor)

Skeletal muscle Na+ channel NaV1.4 mutations


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Cannon, 1997

Computer model of myotonia and paralysis


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Na+ channelopathies


Muscle SCN4A subunit of NaV1.4 Hyperkalaemic periodic paralysisHypokalaemic periodic paralysis

Paramyotonia congenita

Potassium-aggravated myotoniaMyotonia fluctuans

Myotonia permanens

etc

Neuronal SCN1A subunit of NaV1.1(somatic)

Generalised Epilepsy with Febrile

Seizures + (GEFS+),

Severe myoclonic epilepsy ofinfancy (SMEI)

SCN2A subunit of NaV1.2(axonal)

GEFS+

SCN1B 1 subunit


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GEFS+: Generalised epilepsy with febrile seizures plus


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CNS Na+ channel mutations associated with GEFS+


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SCN1B mutation interferes

with the ability of the subunitto modulate channel gating

Wallace et al (1998)


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GEFS+-associated NaV1.1 mutations also interfere with fast inactivation

Lossin et al (2002)


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Remaining questions for Na+ channel mutations:

How do S4 mutations associated with hypokalaemic periodic paralysis cause membrane

depolarisation and [K+]?

What triggers seizure onset?

Why do some SCN1A mutations that affect other kinetic parameters cause epilepsy

Why is the phenotype so variable within GEFS+ families?

How do truncation mutations of SCN1A cause severe myoclonic epilepsy of infancy(SMEI)?


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Ca2+ channelopathies


Muscle CACNA1S subunit of CaV1.1 HypoK periodic paralysisMalignant hyperthermia





Neuronal CACNA1A subunit of CaV2.1(P/Q-type channel)


Episodic ataxia type 2

Spinocerebellar ataxia type 6

Absence epilepsy?CACNA1H subunit of CaV3.2

(T-type channel)

Absence epilepsy


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Ca2+ channel structure

2

1


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Skeletal muscle Ca2+ channel mutations


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Hypokalaemic periodic paralysis-associated mutations of CaV1.1 reduce

Ica, shift voltage sensitivity and slow channel kinetics

but why do they result in depolarisation and episodic paralysis?

Morrill & Cannon (1999)


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Malignant hyperthermia and central core disease are associated with mutations

of the ryanodine receptor gene RYR1

(CACNA1S mutations also found in MH)


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Ca2+ channelopathies


Muscle CACNA1S subunit of CaV1.1 HypoK periodic paralysisMalignant hyperthermia





Neuronal CACNA1A subunit of CaV2.1(P/Q channel)




Absence epilepsy?CACNA1H subunit of CaV3.2

(T-type channel)

Absence epilepsy

4 subunit mutations also reported in association with epilepsy/episodic ataxia


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Familial hemiplegic migraine:

Severe, autosomal dominant, associated with reversible weakness

Other associations: progressive cerebellar ataxia, coma, neuromuscular junction defect

Molecular pathogenesis: or current density left-shifted activation threshold


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Familial hemiplegic migraine: mouse knock-in model

P/Q-type Ca2+ channel-dependent neuromuscular transmission

van den Maagdenberg et al, 2004


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Familial hemiplegic migraine: mouse knock-in model

Cortical spreading depression

van den Maagdenberg et al, 2004


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Prolonged attacks of cerebellar inco-ordination

Associated with progressive cerebellar degeneration

Autosomal dominant


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Jouvenceau et al (2000)

EA2:premature stops, splice-site

mutations, mis-sense mutations

non-functional channel


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Site of CAG expansion

Normal allele: 4-18

SCA6: 19-30

Disease mechanism:

nuclear protein deposition?

altered channel density and activation threshold also reported


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Cl- channelopathies


Muscle CLCN1 ClC1 Myotonia congenitaAR (Beckers)

AD (Thomsens)


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ClC1:

homodimeric with two pores,

major determinant of resting membrane potential


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Membranepotential

Muscle fibres from myotonic goats:

repetitive discharges in response to small depolarising currents

myotonia results from loss of channel function

Adrian & Bryant (1974)

Control Myotonic


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Kubisch et al (1998)

Dominant or recessive behaviour of CLCN1 mutations is

reflected in co-expression studies

Dominant

Recessive


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Loss of function CLCN2

mutations in idiopathic

generalised epilepsy

Haug et al (2003)


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K+ channelopathies


Muscle KCNJ2 subunit of Kir2.1 Andersens syndrome

KCNE3 Accessory subunit MiRP2

(assembles with KV3.4)

HypoK periodic paralysis

Neuronal KCNA1 subunit of Kv1.1(axonal/presynaptic

delayed rectifier)

Episodic ataxia type 1Epilepsy, isolated

neuromyotonia

KCNQ2 M channel subunit Benign familial neonatal

convulsions

KCNQ3


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Muscle K+ channelopathies

Loss of function dominant negative effectAssociation with hypokalaemia poorly understood


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Brief attacks of cerebellar incoordination

Associated with neuromyotonia

Autosomal dominant

Pore

loop


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N C

Extracellular

Intracellular

+

loop

TranslationAssembly

Targeting

Kinetics

Permeation

Wt

R417s

top

Wt+R

417stop

0

0.5

1

Normalisedcurrentamplitude

WtWt+R417stop (scaled)

10 ms-100 mV

0 mV

* *

EA1:

Loss of function

Variable dominant negative effects


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Biervert et al (1998)

KCNQ2 mutation in BFNC causes decreased IK


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Wang et al (1998)

KCNQ2+KCNQ3 heteromultimers make IM channels

25% reduction in IM current is sufficient to cause disease (Schroeder et al (1998)


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Nicotinic receptor channelopathies


Muscle CHRNA1 1 subunit Congenital myasthenic syndrome

CHRNB1 1 subunit

CHRND subunit

CHRNE subunit

Neuronal CHRNA2 4 subunit AD nocturnal frontal lobe epilepsy

CHRNB4 2 subunit

Ni ti i t t th l j ti


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Nicotinic receptor mutations affect:

channel opening

receptor occupancy

expression of the fetal subunit

Nicotinic receptor at the neuromuscular junction


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Slow channel syndrome

Sine et al (1995)

Fast channel syndrome


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Fast channel syndrome

can be associated with congenital joint deformities (arthrogryposis multiplex)

Brownlow et al (2001)
http://www.jci.org/content/vol108/issue1/images/large/JCI0112935.f4.jpeg


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Nicotinic receptorchannelopathies


Muscle CHRNA1 1 subunit Congenital myasthenic syndrome

CHRNB1 1 subunit

CHRND subunit

CHRNE subunit

Neuronal CHRNA2 4 subunit AD nocturnal frontal lobe epilepsy

CHRNB4 2 subunit


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Amplitude Ach sensitivity Desensitisation gCa2+

4 S248F

4 L776ins3

4 S252L

2 V287M

CNS nicotinic receptor mutations: functional consequences

Bertrand et al (2002)

5 out of 5 mutations tested reduced Ca2+-dependent potentiation

Rodrigues-Pinguet et al (2003)


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Presynaptic 42 heteromultimeric nicotinic receptors enhance transmitter release

Gain of function may lower seizure threshold


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Glycine and GABAA receptor channelopathies

Receptor Gene Channel Disease

Neuronal Glycine GLRA1 1 subunit glycine R Familial hyperekplexia

GABAA GABRG2 2 subunit GABAAR GEFS+

GABRA1 1 subunit GABAAR Juvenile myoclonic epilepsy

Compound heterozygosity in


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Amino acid positions are quoted for the rat sequence

R252 E/Q and R271 E/Q - Langosch et. al., 1993R271L/Q - Shiang et. al., 1993; Langosch et. al., 1994I244N - Rees et. al., 1994Y279C - Shiang et. al., 1995K276E - Elmslie et. el., 1996; Lewis et. al., 1998Q266H - Milani et. al., 1996; Moorhouse et. al., 1999R271N/K/H - Lynch et. al., 1997; Langosh et. al., 1994P250T - Saul et. al., 1999R252H and R392H - Vergouwe et. al., 1999

Rea et al (2002)

Compound heterozygosity in

hyperekplexia


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Glycine receptor mutations reduce apparent affinity

K276E

wt

wt

K276E

Lewis et al (1998)


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GABAA receptors: 2 subunit plays a role in

synaptic targeting

benzodiazepine sensitivity ()

zinc sensitivity ()


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GABAA receptor2 subunit mutations associated with GEFS+:

surface expression

deactivation rate

Seizures arise because of loss of function


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GABAA receptor1 subunit mutation associated with JME

current density

EC50

Cossette et al 2002


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Neurological channelopathies:

affect both voltage- and ligand-gated channels

mainly autosomal dominant

loss of function in many cases

Other candidate disorders:

Common migraine

Primary epilepsy

Paroxysmal movement disorders

Conclusions

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Channel Opa Thies