Ion channels

Ion channels in health and
disease
Presenter – Dr. Narendiran. S
Chair Person – Dr. Saraswati Nashi

Introduction
• Signaling in the brain depends on the ability of
nerve cells to respond to very small stimuli.
• Receptors in the eye respond to a single photon of
light.
• Olfactory neurons detect a single molecule of
odorant.
• Hair cells in the inner ear respond to tiny
movements of atomic dimensions.
• These rapid changes are mediated by ion channels.

What are ion channels?
• Protein molecules that
span across the cell
membrane
• Allow passage of ions
from one side to the
other.
• An aqueous pore
becomes accessible after
conformational change.

History
• In the late 1800s, the chemical mechanism underlying nerve
and muscle tissue messaging was not known.
• Ludimar Hermann was able to conclude that nerve and
muscle cells were capable of exhibiting a "self- propagating
wave of negative charge which advances in steps along the
tissue "

History
• In 1880s, Sydney Ringer used a
solution of water and ran it
through the vessels of an
isolated heart from a frog and
discovered that in order for the
heart to continue beating salts
needed to be present in the
water.
• Sodium, calcium, and potassium
salts were important and had to
be in specific concentration
relative to each other.

History
• In 1970s, the existence of ion
channels was confirmed by the
invention of ‘patch clamp’
technique by Erwin Neher and
Bert Sakmann who won a Nobel
Prize for it.
• In 2003, the Nobel Prize was
awarded to American scientists,
Roderick MacKinon and Peter
Agre for their x-ray
crystallographic structure studies
on ion channels.

Why do we need ion channels?
• Ions cannot diffuse across
the hydrophobic barrier of
the lipid bilayer.
• Provide a polar
environment for diffusion
of ions across the
membrane.
Principles of Neural science 5th edition

Specialized functions of ion channels
• Mediate the generation, conduction and transmission of
electrical signals in the nervous system
• Control the release of neurotransmitters and hormones
• Initiate muscle contraction
• Transfer small molecules between cells (gap junctions)
• Mediate fluid transport in secretory cells

Questions to be asked?
• Why do nerve cells have channels?
• How can channels conduct ions at such high rates and still be
selective?
• How are channels gated?
• How are the properties of these channels modified by
various intrinsic and extrinsic conditions?

Ion channels Vs Ion pumps
• Pump moves an ion, or a group of a few ions across the
membrane.
• Undergo series of conformational changes.
• Flow through pumps is 100 to 100,000 times slower.
• Requires energy to function.

Ion channels Ion pumps
Ion channels Vs Ion pumps

Properties
• Ion channels have three important properties:
– Specificity & selectivity for specific ions
– Respond to specific electrical, mechanical, or chemical
signals.
– Conduct ions rapidly across the membrane.
• Conduct upto 100 million ions per second.

How is a channel selective??
• Based on the size of the pore and ions?
• Selectivity filter??
• Is it carrier based??

Armstrong and Hill, Neuron, 1998

How is a channel effective??
Cabral et al, Nature, 2001

Gating

Ligand gated

Phosphorylation gated

Voltage gated & Pressure gated

Functional states

Energy for gating
• In voltage-gated channels the energy is provided by the
movement of voltage sensor membrane’s electric field.
• In transmitter-gated channels gating driven by change in
chemical-free energy that results when the transmitter binds
to channel.
• For mechanically activated channels the energy associated
with membrane stretch is thought to be transferred to the
channel.

Modifiers of gating

Modifiers of gating
• Hence modifiers can be
– Reversible
– Irreversible
• Exogenous regulator binding at a different site.
Binding at the same site as the
endogenous ligand

Structure of ion channels
• Hetero-oligomers from
distinct subunits.
• Homo-oligomers from a
single type of subunit.
• A single polypeptide chain
organized into repeating
motifs
Catterall WA, Science, 1988

Gene superfamilies
• Human genome contains
• Sodium channels - 9 genes
• Calcium channels - 10 genes
• Potassium channels - 75 genes
• Ligand gated channels - 70 genes
• Chloride channels - 12 genes
• Members of each gene superfamily have similar
• Amino acid sequences
• Transmembrane topology
• Physiological functions

Gene superfamilies

Different Genes Encode Different
Pore-Forming Subunits

Different Pore-Forming Subunits
Combine in Various Combinations

Same pore forming subunit combines
with various accesory units

Alternative splicing of Pre-mRNA

Post-Transcriptional Editing of pre-mRNA

Classification
1. Voltage gated –
• Voltage gated sodium channels.
• Voltage gated potassium channels.
• Voltage gated calcium channels.
• Voltage gated chloride channels.
2. Ligand gated –
• Nicotinic" Acetylcholine receptor,
• Ionotropic glutamate-gated receptors and
• ATP-gated P2X receptors, and
• Anion-permeable γ-aminobutyric acid gated GABAA receptor
3. Other gated channels –
• Inward-rectifier potassium channels
• Light-gated channels like channel rhodopsin
• Mechanosensitive channels
• Temperature gated channels
• Cyclic nucleotide gated channels
• Glial channels.
The lancet, 2002

Voltage gated Sodium channel
• Single polypeptide chain.
• Four homologous domains
• 6 transmembrane spanning
alpha helixes.
• Whereas potassium
channels have 4 separate
subunits
Payandeh, Nature, 2011

Sodium channels
• Responsible for the rising
phase of the action potential.
• 10 different genes.
• 4 in the CNS - SCN1A, SCN2A,
SCN3A & SCN8A.
• 3 in PNS – SCN9A, SCN10A &
SCN11A.
• 3 in muscles - SCN4A, SCN5A,
& SCN7A.
Neuroscience Exploring the brain, 4th Edition

Potassium channels
• Selective permeability of potassium channels is a
key determinant of the resting membrane
potential.
• 4 types of potassium ion channels.
– Voltage gated potassium channels
– Calcium-activated K+ channels (KCa)
– Inwardly rectifying K+ channel subunits (Kir)
– 2 pore forming potassium channels (K2P)
Bradley’s neurology in clinical practice 7th edition

Potassium channels

VGKC - Subtypes
• KCNA (Shaker), shal, KCNB
(shab), KCNC (shaw), KCND,
KCNE, KCNF, KCNG, KCNQ,
KCNS, & HCN.
• Disease causing in humans
– KCNA & KCNQ.

VGKC complex
Nature Reviews, Neurology 2017

CASPR2 Complex

Calcium channels
• Essential in neuronal signaling &
synaptic transmission.
• 10 different genes.
• Family 1 - Ca 1.1 to Ca 1.4
mediate the L-type voltage-
dependent calcium.
• Family 2 - Ca 2.1, Ca 2.2 & Ca 2.3
mediates neurotransmission at
fast synapses.
• Family 3 – Ca 3.1, Ca 3.2 & Ca 3.3

Calcium channels - Nomenclature

Voltage gated chloride channels
Dutzler, FEBS Lett, 2004

Ligand- gated
• Channels activated by
neurotransmitter-binding
– Pentameric
• AchR
• GABA
• Glycine
• Serotonin
– Tetrameric
• NMDA
• AMPA
• Kainate
– Trimeric
• ATP gated P2X receptors
Lemoine et al, Chemical Reviews, 2012

Ligand gated ion channels
Chemical Reviews 2012 112 (12), 6285-6318

Acetylcholine Receptor
Miyazawa et al, Nature,2003

Glutamate receptors

Gap junctions
Maeda, Nature, 2009

Mechanoceptors
• Channels can be directly
activated by forces.
• Forces conveyed through
structural proteins.
• Forces conveyed to a force
sensor & then via second
messenger.

TRP channel
• Osmolarity
• pH
• Temperature

TRP channel
Bautista DM et al, 2007. Nature

Ion channels at each step

Synaptic transmission
• Chemical synapses – Neuromuscular junction
• Electrical synapses – Gap junctions

Chemical synapse

Neuromuscular junction

EPSP

IPSP

Functions of Gap junctions
• Transmission across electrical synapses is extremely rapid.
• Speed is important for escape responses.
• Useful for orchestrating the actions of large groups of neurons.
– Tail flip response of a gold fish.
– Inking response of Aplysia(snail)
– Generation of saccades
• Gap junctions are important for myelination
– Enhance communication between schwann cell
– Support layers of myelin
– Promote the passage of nutrients, metabolites and ions.

Potassium spatial buffering
• Extracellular potassium concentrations rise, during periods of
neural activity.
• Increasing extracellular potassium depolarizes neurons.
• Astrocytes fill most of the space between neurons in the brain.
• They have gap junctions and inwardly rectifying (kir) potassium
channels.
• Excess extracellular potassium taken inside and dissipated over
large area of the astrocytes.
• This is called potassium spatial buffering.

Potassium spatial buffering
Devinsky, Orrin et al. Trends in Neurosciences

Inner ear
Kawashima Y et al, 2011. J Clin Invest

Inner ear
Lumpkin EA et al, 1998. J Neurosci

LGIC & pain
Chemical Reviews 2012

• There are several basic principles that apply to
disorder of channel function.
– Location selectivity
– Channel interdependency
– Genetic heterogeneity
– Phenotype heterogeneity.
• Gain of function
• Loss of function
• Dominant negative effect
Ion channels and disease
Celesia et al, clin neurophysio, 2001

Ion channels and disease
• Various mutations
within a single gene
can lead to distinct
clinical syndromes.
• Mutations in different
genes may result in a
single recognized
clinical entity.

Epilepsy & Ion channels
Oyrer et al, Pharmacol Rev, 2018

Spectrum of channelopathies

Inherited channelopathies - Muscle

Inherited channelopathies - Neuronal

Acquired channelopathies

Pain and Channelopathy
Bennett, David L H et al. The Lancet Neurology

Inherited potassium channelpathies

Potassium channel and disease
Proc. Natl. Acad. Sci. USA 96 (1999)

Episodic Ataxia - 1
• Autosomal dominant disease.
• Characterized by ataxic gait & jerking extremity movements that last for
seconds to minutes.
• Also called episodic ataxia with myokymia
• Provoking factors - motion & exercise.
• Episodic failure of excitation of cerebellar neurons & sustained
hyperexcitability of the peripheral motoneurons.
• Treatment - Carbamazepine

Mutations in EA - 1

Benign familial neonatal convulsions
• Incidence is about 1 in 100,000 .
• Seizures begin a few days after birth.
• Most patients remit by the age of 4 months
• 16% of patients continue to suffer seizures in adult life.
• Mutations in KCNQ2 & KCNQ3.
• carbamazepine and phenytoin are generally effective in treating
BFNC.

Mutations in BFNC

• Isaac’s syndrome
• Morvan’s syndrome
• VGKC complex encephalitis
Acquired potassium channelopathies

Isaac’s syndrome
• Painful muscle cramps, myotonia & hyperhidrosis.
• EMG – Myokymic and neuromyotonic discharges.
• Associated with thymoma.
• Antibodies against VGKC.
• Morvan’s syndrome – Neuromyotonia with fluctuating
delirium.

VGKC encephalitis
CASPR2 Encephalitis LGI1 encephalitis

Sodium channel and disease

GEFS+
• Autosomal dominant febrile seizures.
• Febrile seizures extending beyond 6 years of age.
• Other seizure types – absence, atonic, myoclonic & partial.
• EEG - 2.5- to 4-Hz generalized spike-and-wave or polyspike-
wave discharges.
• SCN1B, SCN1A, SCN2A, SCN9A.

Mutations in GEFS+

Hyperkalemic periodic paralysis
• Episodic weakness precipitated by hyperkalemia.
• Weakness is milder than hypoKPP.
• Respiratory & ocular muscles remain unaffected.
• Frequency – several per day to several per year.
• Attacks are brief – 15 – 60 mins.
• Triggers – Rest after exercise, food with high K, stress & fatigue.
• Myotonia +
• Mutations in SCN4A.
Cannon, SC Neuron, 1991

Mutations in HyperKPP

Paramyotonia congenita
• Paradoxical myotonia, cold-induced myotonia, &
weakness after prolonged cold exposure.
• Warm up phenomenon negative.
• Facial muscles, hand & neck muscles commonly
affected.
• Triggers – cold, stress, rest after exercise.
• Mutations in SCN4A gene.

Primary Erythromelalgia
• Rare autosomal dominant neuropathy.
• Recurrent burning pain, warmth and
redness of the extremities.
• Two missense SCN9A mutations were
recently identified.
• Both mutations cause a hyperpolarizing
shift in the voltage-dependence of
channel activation and slow the rate of
deactivation
• Triggers - Exertion, heating of the
affected extremities, alcohol or caffeine
consumption, and any pressure applied
to the limbs.
Fertelmann CR et al, 2006. Neuron

Inherited calcium channelopathies

Calcium channelopathy

Episodic ataxia type 2
• EA2 also called episodic ataxia without myokymia.
• Age of onset - late childhood or adolescence.
• Triggers - Physical or emotional stress.
• Intermittent attacks of vertigo, headache.
• Interictal nystagmus & impaired vestibulo-ocular reflex.
• Attacks may be prolonged, lasting for hours and sometimes days.
• Neuroimaging - cerebellar atrophy.
• Treatment - Acetazolamide therapy.
Newsome-Davis et al, 2003. Ann NY Acad Sci

Familial Hemiplegic Migraine
• Autosomal dominant.
• Migraine characterized by lateralized motor weakness.
• 3 classes – FHM type 1, 2 & 3.
• FHM 1 – Severe type.
• Auras always involve additional symptoms including sensory,
visual, & language disturbances.
• Aura may last for days with fever, meningismus and cerebellar
signs.
• FHM 2 & FHM 3 – No cerebellar signs. Less severe.

Spino cerebellar ataxia - 6
• Autosomal dominant cerebellar ataxia.
• CAG trinucleotide repeat in the gene coding for the alpha1A-
subunit of the voltage dependent calcium channel.
• Mean of age at onset – 50.
• Prominent cerebellar signs.
• Intermittent diplopia.
• Eye signs – Dysmetria, impaired smooth pursuits, impaired ocular
movements, peripheral neuropathy.

Acquired calcium channelopathies

Lambert – Eaton Myasthenic syndrome
• Produces weakness by obstructing neuromuscular
transmission.
• Pathology – Presynaptic.
• Autoantibodies against P/Q type VGCC.
• Autonomic dyfunction +
• Autoantibodies don’t cross the BBB.
• Paraneoplastic to SCLC.

Paraneoplastic cerebellar degeneration
• Rapid progressive ataxic syndrome.
• Commonly occurs in cases of breast, ovarian, and lung
malignancies.
• Purkinje cell loss is the pathological hallmark.
• Anti-P/Q-type VGCC antibodies.
• May or maynot have neuromuscular involvement.
• No episodic symptoms.

Chloride channelopathies
• Autosomal dominant – Thomsen’s disease
• Autosomal recessive – Becker’s disease.
• Main feature is myotonia - delayed muscle relaxation after contraction.
• Pronounced after a period of rest, prominent in the legs.
• Warm up phenomenon positive.
• Recessive – More common, develop progressive myopathy, severe
disease.
• Pathophysiology
– Mutation in CLCN1 gene coding for chloride channel.
– Diminished sarcolemmal chloride conductance.

Comparison of channelopathies

• Mediate intercellular communication
• Converts the binding of a neurotransmitter released from
the presynaptic terminal into an ion flux in the postsynaptic
membrane.
• Have orthosteric-binding site for the NT & an ion channel.
• Well-established role in neurotransmission.
• Conventional neurotransmitters - glutamate, acetylcholine,
glycine, ATP, serotonin & GABA.
Ligand gated Ion channels

Alzheimer’s disease
• Neurodegenerative disorder characterized by progressive
cognitive decline.
• Loss of neurons & cholinergic synapses in the basal forebrain,
cerebral cortex, & hippocampus.
• Extracellular accumulation of senile plaques.
• Formation of neurofibrillary tangles composed of
hyperphosphorylated tau protein.
• Aβ neurotoxicity is due in part to complex interactions with
nAChRs.

Alzheimer’s disease

ADNFLE
• Clusters of brief partial seizures that occur during light sleep.
• Hyperkinetic tonic stiffening and clonic jerking movements.
• Aura may precede seizures - somatosensory, sensory, & psychic
phenomena.
• ADNFLE is often mistaken for benign nocturnal parasomnia or
night terror.
• Nocturnal video polysomnography is very useful.
• Point mutation in the nAChR α4-subunit

Congenital myasthenic syndromes
Engel AG, Curr Opin Pharmacol 2005

Myasthenia Gravis
Drachman, Trends Neurosci 1983

Hereditary hyperekplexia
• Human startle disease – exaggerated startle response.
• Normal startle - blinking, grimacing, neck flexion, and arm
abduction & flexion.
• Overreaction to unexpected visual, auditory, or tactile stimuli.
• Consciousness is preserved during the attacks.
• May be cause apneic episodes & death.
• Mutations in GLRA1 and GLRB gene.

Mutations in glycine receptor

GABA receptors
• Mutations encoding – α1 subunit of GABA A receptors
– Autosomal dominant
– Juvenile myoclonic epilepsy,
– Sporadic childhood absence seizures
– Idiopathic generalized epilepsy.
• Pathophysiology
– Loss-of function of GABA A receptors
– Decreased sensitivity to GABA
– Reduced total cell surface expression
– Increased retention of the receptor in the endoplasmic
reticulum

Rasmussen’s encephalitis
• Etiology: Glutamate receptor autoimmunity.
• Age of onset: Variable, usually young children
• Clinical characteristics: Intractable focal epilepsy, often
with epilepsia partialis continua (EPC), and progressive
hemiparesis followed by progressive intellectual decline.
• EEG: Slowing ipsilateral to hemiatrophy. EPC may not
have EEG correlate.

Glial channelopathy
• Only one glial channelopathy - X-linked Charcot-Marie-Tooth
disease.
• Characterised by a progressive motor and sensory neuropathy.
• Mutations of the connexin 32 gene.
• Connexin 32 is expressed in Schwann cells.
• Due to impaired gap junction function causing disruption of
cytoplasmic homeostasis in schwann cells.
The lancet, 2002

Conclusion
• In all cells ion channels permit the flow of ions across an otherwise impermeable
membrane.
• In nerve and muscle cells ion channels are important for controlling the rapid
changes in membrane potential.
• Channels are also important targets in various diseases.
• The genetic channelopathies have helped us to understand the pathogenesis of
several classes of disease.
• Many other ion channels are likely to be implicated in neurological diseases in
the future.
• Phenotypic range associated with individual channels is likely to be broader.

Ion channels

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