MOLECULAR BASIS OF K

CONDUCTION & SELECTIVITY IN ION

CHANNEL-ROLE IN AUTISM
SPECTRUM DISORDER(ASD)
PRESENTER:- NATNAEL HABTAMU

OUTLINE
Introduction
K-channel
Structure and conduction
Selectivity
Types

ASD

INTRODUCTION
Simple diffusion is either too slow or
impossible
But life has provided us is Membrane
Channel Proteins

INTRO..MEMBRANE CHANNELS
Dimers, trimers, tetramers, or pentamers of protein subunits
For example channels for Na, K, Mg, and glutamate

Most membrane channels are gatedthat is, in response to a

triggering signal,

INTRO..MEMBRANE CHANNELS
So how do these channels make it easier for the ions to cross the
membrane?
Water filled to stabilize ions.
Hydrated ions can simply diffuse into the pore and cross the membrane.

The Polar properties of the amino acid residues

K CHANNEL STRUCTURE AND CONDUCTION

Tetrameric
Fouridentical copiesof the K+channel protein,

K+ channel protein: either 6 transmembrane voltage

gated -helicesor 2 transmembrane -helices
(bacterial or non-v.gated)
Helices 5 & 6

extracellular space

The interveningH5segment of each of the 4 copies of

the protein.

H5

Helices 1-4function as avoltage-sensing domain,

withhelix #4having a special role in voltage sensing.

This domain is absent in K+channels that are not

voltage-sensitive.

+
4

+
N
cytosol

OVERALL STRUCTURE BACTERIAL KCSA

CHANNEL
V shaped tetramer
The 1st channel studied for
selectivity from Streptomyces
lividans.
3 segments:
1.5 nm Selectivity filter
1.0 nm Cavity
1.8 nm Internal pore

K-CHANNEL SELECTIVITY
4 H5s consensus sequence(Thr-ValGly-Tyr-Gly)
This consensus sequence forms selectivity
filter

Dehydration to pass through selectivity

filter
Polar oxygen atoms of the protein as
surrogate water

K-CHANNEL SELECTIVITY
At a given time, 2 K ions at the selectivity filter
How is it selective:
An ion must be capable enough loose water and be balanced
with oxygen while at the same time pass through the channel.
Also the energy used for dehydration should be balanced (e.g.
energy of oxygenation)

The ion while going through all this process must be able to
hold the channel open

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K-CHANNEL SELECTIVITY
Na+, being smaller than K+,
would be able to interact with oxygen atoms on
only one side of the channel.
Removal of water --- not stabilized by oxygen

Thus for Na+, selectivity filter must undergo a

conformational change to a partly collapsed
state.

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TYPES OF K-CHANNELS
Inwardly rectifying - passes current (positive charge) more easily in
the inward direction (into the cell).
Tandem pore domain Set the negative membrane potential of
neurons
Voltage-gated potassium - arevoltage-gated ion channels that open
or close in response to changes in thetransmembranevoltage
Based on amino acid sequence: Kv1-Kv12

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AUTISM SPECTRUM DISORDERS (ASDS)

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AUTISM SPECTRUM DISORDERS (ASD)

Group of Heterogeneous Neuro Developmental Disorders
Usually a childhood disorder (before age three)
If ASD caused by ion channel defects -cASDschannelASD
Thought to be highly genetic
Deleterious mutations in several K+channel types

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AUTISM SPECTRUM DISORDERS (ASD)

Characterized mainly by
impaired social skills
verbal and nonverbal communication difficulties
narrow, obsessive interests or repetitive behaviors

no cure exists and no drugs

Children respond well to specialized behavioral therapies

Nia foundations
Joy center

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AUTISM SPECTRUM DISORDERS (ASD)

Channel ASDs
Kv 4.2
Mainly found in the hippocampus
Useful in synaptic maturation and network refinement.
It also regulates the threshold for action potential initiation and repolarization

Kir 4.1(Inwardly-rectifying) predominantly expressed in glial cells

help maintain the ionic and osmotic environment in the extracellular space

So mutation in the genes encoding these channels results in problems

of transmission, network impairment and plasticity .

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AUTISM SPECTRUM DISORDERS (ASD)

For instance.Kv4.2: Neuronal
Regulates the threshold for action potential initiation and repolarization,
frequency-dependent AP broadening and back-propagation of AP.
Genetic mutation : gain-of-function: slows channel inactivation leading
to greater channel availability in response to depolarization
phenotype: display increased susceptibility to convulsion stimulation.

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https://spectrumne
ws.org/news/targetin
g-potassium-channeleases-autismsymptoms-in-mice/

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20 MINUTES SEMINAR.NOBEL PRICE?

Dr. Roderick MacKinnon: 2003 Nobel price in chemistry

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REFERENCE:
The Structure of the Potassium Channel: Molecular Basis of K1Conduction and
SelectivityDeclan A. Doyle, Joa o Morais Cabral, Richard A. Pfuetzner,Anling Kuo,
Jacqueline M. Gulbis, Steven L. Cohen,Brian T. Chait, Roderick MacKinnon*
POTASSIUM CHANNEL STRUCTURES Senyon Choe
MacKinnon R., 'Potassium channels and the atomic basis of selective ion conduction
(Nobel Lecture)', Angew Chem Int Ed Engl. 2004 Aug 20;43(33):4265-77.
Reginald H. Garrett; Biochemistry 4 th edition
http://lettsscience.com/2012/07/13/pores-and-selectivity-filters /
https://www.genome.gov/25522099

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