This document presents a summary of a student's assignment on voltage-gated ion channels. It begins with an introduction to membrane ion channels and an outline of the presentation. It then discusses the basic structure and mechanism of voltage-gated ion channels, describing how the voltage sensor detects changes in membrane potential. The four major types of voltage-gated channels are identified as sodium, calcium, potassium, and chloride channels. Key details are provided about the structure and function of sodium and potassium channels.

1. 05/02/2020 Molecular pharmacology, BY bantayehu 1
Presented to: Dr.Wubayehu ( PHD in
pharmacology; UoG)
Presented by: Bantayehu A
2019 GC
ASSIGNMENT PRESENTATION ON
VOLTAGE GATED ION CHANNELS

2. BANTAYEHU A 2
 Introduction of membrane potassium ion channels
 Basic structure of voltage gated ion channels
 mechanism of voltage gated ion opening channel
 Common (Major) types voltage gated ion channel
 Physiological effects of voltage gated ion channels
 major disease of human associated with voltage gated channel
(channelopathies)
PERSENTATION OUTLINE

3. OBJECTIVE
After the end of this presentation students will
be able to;
Define voltage gated ion channel
Understand mechanism of voltage gated ion channel opening
Enumerate the four types of voltage gated ion channel
Describes the structure and effects of voltage gated ion channel
Realize the concept of channelopathies
BANTAYEHU A 3

4. INTRODUCTION
Ion channels are molecular machines that serve as principal
integrating and regulatory devices for the control of cellular
excitability
Ion channels were first studied and are best known in connection to
the nervous system, especially in the generation and propagation of
action potentials.
There are two major types of ion channel
1. voltage gated and
2. Ligand gated
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5. Cont…
 Voltage-gated ion channels are a class of trans membrane
proteins that form ion channels that are activated by changes in
the electrical membrane potential near the channel.
 The membrane potential alters the conformation of
the channel proteins, regulating their opening and closing
 The opening and closing of the channels are triggered by
changing ion concentration, and hence charge gradient,
between the sides of the cell membrane
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6. CONT…
Voltage gated ion channels open in response to voltage (i.e. when
the cell gets depolarized) where as
ligand gated channels open in response to a ligand (some
chemical signal) binding to them.
The Voltage-gated ion channels are responsible for
 maintaining neuronal homeostasis and function
 secretion,
 endocytosis,
 muscle contraction,
 synaptic transmission,
 ciliary control,
 fertilization, etc.
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7. CONT….
Electrical signals control
 contraction of muscle,
 secretion of hormones,
 sensation of the environment,
 processing of information in the brain, and
 output from the brain to peripheral tissues.
In excitable cells, electrical signals also have an important
influence on :
I. intracellular metabolism and signal transduction,
II. gene expression, protein synthesis and targeting, and
III. protein degradation.
The voltage-gated ion channels are the molecular targets for a
wide range of potent biological toxins, including the gating
modifier toxins that alter the kinetics and voltage dependence of
their activation and inactivation.
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8. DEFINITION OF VOLTAGE GATED ION CHANNEL
Any ion channel that opens and closes in response to changes in
electrical potential across the cell membrane in which the channel
is situated
Voltage-gated ion channels are multisubunit protein complexes
that respond to changes in membrane potential with
conformational changes that lead to
 gating, or opening and
 closing, of an ion-selective trans membrane pore and
 propagation of action potentials in electrically excitable cells.
Molecular dynamics simulations have become a useful tool to
study the molecular basis of ion transport in atomistic models of
voltage-gated ion channels.
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9. VOLTAGE-GATED CHANNEL STRUCTURE
Voltage-gated ion channels are integral membrane proteins.
They have a similar molecular structure that includes a repeating
motif with six membrane-spanning alpha helices
There is also a pore loop that contributes to the selectivity filter
and a charged domain that acts as a voltage sensor.
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10. cont…
During depolarization the inner face of the cell membrane
becomes more positive and
the voltage sensor (which carries a positive charge) is thrust
upwards through the membrane by electrostatic repulsion.
This movement induces a conformational change in the channel
complex which opens the pore.
Conductance changes steeply, increasing 150-fold with a 10 mV
shift in membrane potential.
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11. STRUCTURE AND FUNCTION
Voltage-dependent channels
are made of three basic parts:
1. Voltage sensor
2. The pore or conducting
pathway and
3. Selectivity filter
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12. Cont…
Voltage gated ion channels consist of a highly Processed:
 Principal α subunit, associated with
auxiliary β subunits.
The pore-forming α subunit is sufficient for functional expression, but the
kinetics and voltage dependence of channel gating are modified by the β
subunits
The α subunits are organized in four homologous domains (I-IV) each
with six transmembrane segments (S1-S6)
- 24 transmembrane segments in total.
The pore forming segments are formed by S5 and S6.
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14. Discussion on the picture
(A)The channel subunits are composed of six membrane-spanning
alpha-helices (S1–S6) together with
 a pore loop that is responsible for ion selectivity.
 The charged domain (S4) acts as a voltage sensor;
(B) The voltage-gated sodium channel consists of a single large
protein with four repeating motifs (each with six membrane-
spanning domains and a pore loop).
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15.  In this diagram, a single
transmembrane domain is
shown as the voltage sensor
that operates the gate.
 The S4 segment of voltage
gated channel is the voltage
sensor that is responsible for
changing conformation as the
voltage changes.
 All voltage gated channels
have this S4 segment.
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16. HOW DOES VOLTAGE OPEN CHANNELS?
Voltage-gated ion channels contain intrinsic voltage sensors.
ion channels typically are closed at the resting membrane potential
but open upon membrane depolarization.
These channels detect changes in electric potential across the
membrane through a domain responsible for sensing voltage.
The voltage sensor spans the membrane and is thus exposed to the
electric field across the phospholipid bilayer.
Charged residues in this sensor move in response to changes in
membrane potential and trigger conformational changes of the
channel.
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17. MECHANISM OF VOLTAGE GATED ION CHANNEL
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18. Cont…
The S4 segment corresponds to the voltage sensor.
In the voltage-gated ion channels, these gating charges correspond
to several basic, positively charged residues at every third position
in the S4 transmembrane alpha helix.
Each of the four subunits or pseudo subunits of these channels
contain one voltage sensor, and depolarization of the cell
membrane exerts an electrostatic force on the gating charges that
causes the S4 segment to move outward.
The concerted movement of the four S4 segments cooperatively
opens the channel gate
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19. TYPES OF VOLTAGE GATED ION CHANNEL
 There are several types of voltage-gated channel, each allowing
the selective passage of a particular ion
 The most important voltage-gated ion channels in myocytes are
those selectively permeable to Na+, K+, Ca2+, and Cl
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20. THE FOUR IMPORTANT VOLTAGE GATED ION CHANNEL
1. VOLTAGE GATED SODIUM CHANNELS- 9 members
 Responsible for membrane depolarization in action potential
generation
2. VOLTAGE GATED CALCIUM CHANNELS- 10 members
Play an important role in both linking muscle excitation with
contraction as well as neuronal excitation with transmitter
release.
3. VOLTAGE GATED POTASSIUM CHANNELS- 40 members
 Role in repolarization of cell membrane after AP
4. VOLTAGE GATED CHLORIDE CHANNEL
Are present in every type of neuron, where they control
excitability, restore the resting membrane potential and help
regulate cell volume are a superfamily of poorly understood
ion channels.
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21. 1. VOLTAGE GATED SODIUM CHANNEL
Sodium channels play a central role in physiology:
 they transmit depolarizing impulses rapidly throughout cells and
cell networks, thereby enabling co-ordination of higher
processes ranging from locomotion to cognition.
Elucidation of their fundamental properties in the squid axon
launched modern channel theory.
The work of Hodgkin and Huxley on sodium channels
revolutionized electrophysiology by elegantly dissecting the
elementary processes of gating and permeation
More recently, sodium channels were the first voltage-dependent
ion channels to be cloned
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 These channels are responsible for the rapid influx of sodium ions
during the action potential in nerve, muscle, and endocrine cells.
 Sodium channels mediate fast depolarization and conduct
electrical impulses throughout
 nerve,
 muscle and
 heart.
 Sodium channels have a modular architecture, with distinct
regions for the pore and the gates.
 At a molecular level, sodium channels are not static: they move
extensively in the course of gating and ion translocation

23. Cont…
 Sodium channels bind local anaesthetics (E.g.. LIDOCANINE) and
various toxins.
 In some cases, the relevant sites have been partially identified.
 Sodium channels are subject to regulation at the levels of
transcription,
subunit interaction and
post-translational modification (notably glycosylation
phosphorylation
Na+ channels consist of various subunits, but only the principal (α)
subunit is required for function.
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24. Cont…
the α subunit has a modular architecture: it consists of four
internally homologous domains (labelled I-IV), each of which
contains six transmembrane segments and resembles a single α
subunit of a voltage-dependent K+ channel.
The four domains fold together so as to create a central pore
whose structural constituents determine the selectivity and
conductance properties of the channel
The sodium channels open rapidly in response to initial
depolarization of the axon plasma membrane, allowing sodium
ions (Na+) to flood in
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25. Cont…
 and a channel-inactivating segment moves to block the channel and
allow the channel protein to revert to its resting state.
 The sodium channel protein has positively charged voltage-sensing
regions, which move towards negative charges on the outer surface of
the membrane when the latter becomes depolarized.
 This opens the channel, allowing passage of sodium ions.
 Within a millisecond of channel opening, the voltage-sensing region
returns to its original location
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26. General architecture of voltage-gated channels (Na+
and Ca2+
).The “+” or “-“ signs
indicate charges that have been implicated in voltage sensing.
The voltage sensor is a region of the protein bearing charged amino
acids that relocate upon changes in the membrane electric field
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27. con
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28. PHYSIOLOGICAL EFFECT VOLTAGE GATED NA CHANNEL
Dysfunctional NaV channels are implicated in various disorders,
which makes them potential drug targets for their treatment .
Thus a molecular-level understanding the operation of NaV
channels is an important problem in physiology with ramifications
in medicine and pharmacology
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29. Cont…
Voltage-gated sodium and calcium channels (NaV and CaV
channels, respectively) are important mediators of many
physiological functions, including
– propagation of electrical signal,
– cell excitability,
– gene transcription,
– secretion and synaptic transmission,
– plasticity and muscle contraction .
As might be expected,Na+ channel gives rise to action potentials
of long duration and is one of the targets of:-
 local anesthetics such as benzocaine and lidocaine
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30. 2. VOLTAGE GATED POTASSIUM CHANNEL
Voltage-gated K+ channels are one of the key components in
generation and propagation of electrical impulses in nervous
system.
Upon changes in transmembrane potential, these channels open
and allow passive flow of K+ ions from the cell to restore the
membrane potential
The largest and most diverse class of voltage-gated ion channels
are the K+ channels .
 Nearly 100 K+ channel genes are now known, and
 these fall into several distinct groups that differ substantially
in their gating properties
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31. STRUCTURE OF POTASSIUM CHANNELS
Potassium channels contain :
 principal subunits (often called a-subunits), which determine
the structure of the channel, and
 auxiliary subunits (often called b-subunits), which can modify
the properties of the channel.
Most of the known principal subunits express in heterologous
expression systems as functional homo-multimeric channel
complexes.
Potassium channel a-subunits fall into at least eight families based
on predicted structural and functional similarities
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32. Cont…
 Three of these families
1. Kv,
2. ether-a-go-go-related gene (EAG), gene (KCNH2)
3. and KQT share a common motif of six transmembrane
(TM) domains and are primarily gated by voltage
 Two other families,
1. CNG
2. SK/IK, also contain this motif but are gated by cyclic
nucleotides and calcium, respectively.
 Three other families of potassium channel Alpha -subunits have
distinct patterns of TM domains.
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33. Cont…
 Kir channels belong to a structural family two TM domains.
 An eighth functionally diverse family K2p channels contains two
tandem repeats of this inward-rectifier motif
 Thus, these families could be mainly divided into three groups
termed as
 voltage-gated six TM potassium channels (Kv channels),
 calcium-activated six/seven TM potassium channels (Kca
channels), and
 two TM potassium channels, respectively.
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34. voltage-gated six trans membrane potassium channels
 Voltage-gated potassium channels (Kv channels) are the largest
group in potassium channel family, which in humans are encoded
by 40 genes and
are divided into 12 subfamilies. These include
Kv1 (KCNA), Kv2 (KCNB), Kv3 (KCNC), Kv4 (KCND), Kv7
(KCNQ, also named KQT), Kv10, Kv11 (KCNH, also named
EAG) and Kv12.
 Kv5, Kv6, Kv8, and Kv9 channels are not functional alone;
 they co-assemble with Kv2 subunits and modify their function.
 These family members share six TM and are gated by voltage
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35. Cont…
• All mammalian Kv channels consist of four a-subunits, each
containing six TM a-helical segments, S1–S6, and a P-loop,
which are arranged circumferentially around a central pore as
I. Homotetramers or
II. hetero-tetramers
• The pore domain (PD) represents a tetramer of two membrane-
spanning a helixes that are connected with each other via a P-
loop, which is responsible for potassium ion selectivity.
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36. Cont…
The PD contains a channel gate, which controls ion permeation.
The structure of the gate is a bundle ofovercrossing a helixes at
the cytoplasmic entryway of the channel pore.
These a helices correspond to the S6 helix of Kv channels.
In Kv channels, the pore is covalently linked to four specialized
membrane-embedded peripheral functional modules, voltage-
sensing domains (VSDs), which are comprised of S1–S4
membrane-spanning segments, with four positively charged
arginine residues in the S4 helix
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37. Cont…
 Voltage-sensing domains are connected to the PD by
 a linker, known as S4–S5 linker at the cytoplasmic side of the
membrane.
 The VSD-PD assembly represents an exquisite molecular
electromechanical coupling device, which converts potential
energy of the membrane electric field into the mechanical work
needed to control the selective permeation of potassium ions
 Several functional studies indicate that concordance between the
S4–S5 linker and distal S6 region of the PD is important for
transmission of conformational changes from VSDs to PD
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38. A) Schematic representation of transmembrane (TM) topology of Kv
channel a-subunits containing six TM segments with the pore
region formed by S5 and S6 segments.
B) Structure of the tetrameric assembly of the Kv channel.
Chem Biol Drug Des 2014; 83: 1–26
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40. Structural Domains Found in Voltage-gated K Channels
 Cloning of the Shaker channel provided the first opportunity to analyze
the primary amino acid sequence of a K channel.
 Voltage-gated Na or Ca channel proteins are comprised of a large
continuous sequence that codes for four repeated elements, each of
which are homologous to one Shaker protein (Figure 1A).
 A single one of these structural elements is believed to span the
membrane six times (Figure 1B)
 It is now firmly established that four Shaker proteins are needed to
assemble a functional voltage-gated K channel (KV), thus producing a
structure similar to voltage-gated Na and Ca channels, one that has been
broken up into subunits.
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41. 3. VOLTAGE GATED CALCIUM CHANNEL
Voltage-gated calcium channels mediate calcium influx in
response to membrane depolarization and regulate intracellular
processes such as contraction, secretion, neurotransmission.
Like sodium channels, the α1 subunit of voltage gated calcium
channels is organized in four homologous domains (I-IV), with six
trans membrane segments (S1-S6) in each.
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42. Calcium Cont…
An intracellular β subunit and a transmembrane, disulfide-linked
α2β subunit complex are components of most types of calcium
channels
A γ subunit has also been found in skeletal muscle calcium
channels, and related subunits are expressed in heart and brain.
There are several different kinds of high-voltage-gated calcium
channels (VGCCs).
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43. Calcium Cont…
1. N-type channel (Most often found throughout the brain and
peripheral nervous system).
2. P/Q-type channel (Purkinje neurons in the cerebellum)
3. L-type (Skeletal muscle, smooth muscle, bone (osteoblasts),
ventricular myocytes (responsible for prolonged action potential in
cardiac cell), dendrites and dendritic spines of cortical neurones).
Notice: L-type channels are responsible for excitation, contraction
coupling of skeletal, smooth, and cardiac muscle and for
hormone secretion in endocrine cells
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44. Schematic depictions of the three pore-forming α-subunits of:
(a) sodium (Na) channel; (b) L-type calcium channel; (c) Kv channel
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45. CHANNELOPATHIES
Channelopathies are diseases that develop because of defects in ion
channels caused by either genetic or acquired factors.
The following inherited channelopathies are described.
(1) Sodium channelopathies:
 familial generalized epilepsy with febrile seizures plus,
 hyperkalemic periodic paralysis,
 paramyotonias, (hypokalemic periodic paralysis)
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46. Channelopathies cont…
(2) potassium channelopathies:
 benign infantile epilepsy, episodic ataxia type 1;
(3) calcium channelopathies:
 episodic ataxia type 2, pinocerebellar ataxia type 6,
 familial hemiplegic migraine,
 hypokalemic periodic paralysis,
 malignant hyperthermia syndrome, congenital stationary
 night blindness;
(4) Chloride channelopathies:
 myotonia congenitas; (delayed relaxation (prolonged
contraction) of the skeletal muscles
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47.  Voltage gated ion channels open in response to voltage (i.e. when the cell gets
depolarized)
 Voltage-dependent channels are made of three basic parts: Voltage sensor,
The pore or conducting pathway and Selectivity filter
 ion channels typically are closed at the resting membrane potential but open
upon membrane depolarization.
 Voltage gated ion channels consist of a highly Processed:
1. α subunit (Principal) associated with
2. β subunits(auxiliary)
 The most important voltage-gated ion channels in are those selectively
permeable to Na+, K+, Ca2+, and Cl
 The largest and most diverse class of voltage-gated ion channels are the K+
channels .
 Channelopathies are diseases that develop because of defects in ion channels (
voltage gate ion channels) caused by either genetic or acquired factors.
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SUMMARY

48. Reference
1. William A. Catterall and Teresa M. Swanson ; Structural Basis for Pharmacology of
Voltage-Gated Sodium and Calcium Channels ; April 6, 2015
2. Carlo Guardiani, et al, Different roles for aspartates and glutamates for cation permeation
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3. Anna Fernández-Falgueras,et al, Cardiac Channelopathies and Sudden Death:29 January
,2017
4. Rudiger Kohling and Jakob Wolfart; Oscar Langendorff Institute of Physiology,
University of Rostock, Rostock 18057, Germany, May 9, 2016
5. https://www.slideshare.net/ValenciaFernandes1/ion-channels-71093061,2017
6. Somayeh Mahdavi, and Serdar Kuyucak; Mechanism of Ion Permeation in Mammalian
Voltage-Gated Sodium Channels: August 14, 2015
7. Rían W. Manville1, Direct neurotransmitter activation of voltage-gated
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8. Paul Johns , Electrical signalling in neurons; 2014 page 71-80
9. Diane Lipscombe, Cecilia P. Toro, in From Molecules to Networks ions of this important
class of membrane proteins. (Third Edition), 2014
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49. REFERENCE CONT…
10. Brooke RE Association of potassium channel Kv3.4 subunits with pre-
and postsynaptic structures in brainstem and spinal cord; Neuroscience.
2004;126(4):1001-10.
11. Jason Tien,et al, Molecular Properties of Ion Channels; in From Molecules to Networks (Third Edition),
2014
12. M.N. Rasband, J.S. Trimmer, in Encyclopedia of Neuroscience, 2009
Voltage-gated ion channels are responsible for the generation
13 Chuan Tian, Potassium Channels: Structures, Diseases, and
Modulators; Chem Biol Drug Des 2014; 83: 1–26
14 Selvarajan Sandhiya & Steven Aibor Dkhar, Review ArticlePotassium channels in health, disease
& development of channel modulators Indian J Med Res 129, March 2009, pp 223-232
15. Celesia GG, Disorders of membrane channels or channelopathies; 2001
Jan;112(1):2-18
16. William A. etal, Voltage-gated Ion Channels and Gating Modifier Toxins , Department of
Pharmacology, University of Washington, 2007
17. https://www.encyclopedia.com/science/dictionaries-thesauruses-pictures-and- press releases/voltage-
gated-ion-channel
18. https://www.ncbi.nlm.nih.gov/books/NBK10883
19. Mario M., et al, Prokaryotic K+ channels: From crystal structures to
diversity; July, 2005
20. J ohn C. Foreman,& Torben Johansen, Textbook of receptor pharmacology; 2nd ed.; 2003
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