1. ION CHANNELS 2. ION CHANNEL RECEPTORS- PRINCIPLES 3. STRUCTURE OF ION CHANNEL RECEPTORS 4. VOLTAGE GATED ION CHANNELS 5. LIGAND GATED ION CHANNELS 6. THANKS

1. ION CHANNEL RECEPTOR
PC-520

2. o Changes in the flux of ions across the plasma membrane are critical
regulatory events in both excitable and non-excitable cells.
o To establish the electrochemical gradients required to maintain a membrane
potential, all cells express ion transporters for Na+, K+, Ca2+, and Cl–.
o Humans express about 232 distinct ion channels to precisely regulate the
flow of Na+, K+, Ca2+, and Cl– across the cell membrane.
o Because of their roles as regulators of cell function, these proteins are
important drug targets.
ION CHANNELS:

3. o Ion channels are pore-forming membrane proteins whose function is
▪ establishing a resting membrane potential,
▪ shaping action potentials and
▪ other electrical signals by gating the flow of ions across the cell membrane,
▪ controlling the flow of ions across membranes, and
▪ regulating cell volume.
o They are often described as narrow, water-filled tunnels that accept only
specific type of ions.
ION CHANNELS:

4. o The diverse ion channel family can be divided into subfamilies based on the
mechanisms that open the channels, their architecture, and the ions they
conduct. They can also be classified as:
▪ Voltage-activated,
▪ ligand-activated,
▪ store-activated,
▪ stretch-activated, and
▪ temperature activated channels.
ION CHANNELS:

11. o In nerve and muscle cells, voltage-gated Na+ channels are responsible for the generation of robust
action potentials that depolarize the membrane from its resting potential of –70 mV up to a potential of
+20 mV within a few milliseconds.
o These Na+ channels are composed of three subunits, a pore-forming α subunit and two regulatory β
subunits.
o The α subunit is a 260-kDa protein containing four domains that form a Na+ ion–selective pore by
arranging into a pseudotetramer shape.
o The β subunits are 36-kDa proteins that span the membrane once.
o Each domain of the α subunit contains six membrane-spanning helices (S1–S6) with an extracellular
loop between S5 and S6, termed the pore-forming or P loop; the P loop dips back into the pore and,
combined with residues from the corresponding P loops from the other domains, provides a selectivity
filter for the Na+ ion.
o Four other helices surrounding the pore (one S4 helix from each of the domains) contain a set of
charged amino acids that form the voltage sensor and cause a conformational change in the pore at
more positive voltages, leading to opening of the pore and depolarization of the membrane.
A. Voltage-Gated Na+ Channels:
Voltage-Gated Channels:
Humans express multiple isoforms of voltage- gated channels for Na+, K+, Ca2+, and Cl– ions.

12. A. Voltage-Gated Na+ Channels:

13. Source: Cameron J Weir, Anaesthesia and Intensive Care Medicine, 21:1 62

14. Two types of ion channels regulated by
receptors and drugs.
(A) voltage-activated Na+ channel
with the pore in the closed and open
states. The pore-forming P loops are
shown in blue, angled into the pore to
form the selectivity filter. The S4
helices forming the voltage sensor are
shown in orange, with the positively
charged amino acids displayed as red
dots.
(B). Ligand-gated nicotinic ACh
receptor expressed in the skeletal
muscle neuromuscular junction. The
pore is made up of five subunits, each
with a large extracellular domain and
four transmembrane helices (one of
these subunits is shown at the left of
panel B).
The helix that lines the pore is shown in
blue. The receptor is composed of two
α subunits and β, γ, and δ subunits.

15. Targets of the voltage-activated Na+ channels:
o Pain neurons are targets for local anaesthetics, such as lidocaine and
tetracaine, which block the pore, inhibit depolarization, and thus block
the sensation of pain.
o Also the targets of the naturally occurring marine toxins tetrodotoxin
and saxitoxin.
o Voltage-activated Na+ channels are also important targets of many
drugs used to treat cardiac arrhythmias.

16. B. Voltage-Gated Ca2+ Channels:
o Voltage-gated Ca2+ channels have a similar
architecture to voltage-gated Na+ channels
with a large α subunit (four domains of five
membrane-spanning helices) and three
regulatory subunits (the β, δ, and γ subunits).
o Ca2+ channels can be responsible for initiating
an action potential (as in the pacemaker cells
of the heart) but are more commonly
responsible for modifying the shape and
duration of an action potential initiated by fast
voltage-gated Na+ channels.

17. B. Voltage-Gated Ca2+ Channels:
o These channels initiate the influx of Ca2+ that stimulates the release of neurotransmitters in
the central, enteric, and autonomic nervous systems and that control heart rate and impulse
conduction in cardiac tissue.
o The L-type voltage-gated Ca2+ channels are subject to additional regulation via
phosphorylation by PKA.
o Voltage-gated Ca2+ channels expressed in smooth muscle regulate vascular tone via the
activity of the Ca2+/calmodulin-sensitive MLCK.
o Ca2+ channel antagonists such as nifedipine, diltiazem, and verapamil are effective
vasodilators and are widely used to treat hypertension, angina, and certain cardiac
arrhythmias.

18. o Voltage-gated K+ channels are the most numerous and structurally diverse members of
the voltage-gated channel family and include:
▪ the voltage-gated Kv channels, the inwardly rectifying K+ channel, and
▪ the tandem or two-pore domain “leak” K+ channels.
o The inwardly rectifying channels and the two-pore channels are voltage insensitive,
regulated by G proteins and H+ ions, and greatly stimulated by general anaesthetics.
o Increasing K+ conductance through these channels drives the membrane potential more
negative (closer to the equilibrium potential for K+); thus, these channels are important
in regulating resting membrane potential and restoring the resting membrane at -70 to -
90 mV following depolarization.
C. Voltage-Gated K+ Channels:
Ref: Goodman and Gillman Pharmacology Book

19. o Channels activated by the binding of a ligand to a specific site in the channel protein have a
diverse architecture and set of ligands.
▪ Excitatory neurotransmitters such as ACh or glutamate or AMPA or NMDA and
▪ inhibitory neurotransmitters such as glycine or GABA.
o Activation of these channels is responsible for the majority of synaptic transmission by neurons
both in the CNS and in the periphery.
o In addition, there are a variety of more specialized ion channels that are activated by intracellular
small molecules and are structurally distinct from conventional ligand-gated ion channels.
▪ members of the Kv family, such as the HCN (Hyperpolarisation-activated, cyclic
nucleotide-gated) channel expressed in the heart that is responsible for the slow
depolarization seen in phase 4 of atrioventricular and sinoatrial nodal cell action
▪ the CNG (Cyclic nucleotide-gated) channel that is important for vision.
▪ IP3-sensitive Ca2+ channel responsible for release of Ca2+ from the ER and the
sulfonylurea “receptor” (SUR1) that associates with the Kir6.2 channel to regulate the KATP
in pancreatic β cells. The KATP channel is the target of oral hypoglycaemic drugs such as
sulfonylureas and meglitinides that stimulate insulin release from pancreatic β cells and are
used to treat type 2 diabetes
Ligand-Gated Channels:
Ref: Goodman and Gillman Pharmacology Book

21. o The pore opening in the
channel measures about 3
nm, whereas the diameter
of a Na+ or K+ ion is only
0.3 nm or less.
o The activation of the
nicotinic ACh receptor
allows passage of both Na+
and K+ ions.

25. THANK YOU