Voltage-Gated Ion Channels (Dr Prole and Rahman) - Revision Notes
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Course
Pharmacology
Institution
Cambridge University (CAM)
Detailed revision notes from lecture course on voltage-gated ion channels taught by Dr Prole and Rahman, University of Cambridge, with additional reading and insights from key publications summarised.
2015 (Paper 1) Describe mechanisms that regulate the trafficking of voltage-gated ion
channels.
2015 (Paper 2) ‘Voltage-gated potassium channels fine-tune the electrical firing properties
of neurons’. Discuss
2014 (Paper 1) Potassium-selective ion channels form a large and diverse family. How is
diversity achieved? Provide examples of its importance in neuronal function?
2013 (Paper 2) Crystal structures of voltage-gated ion channels have provided tremendous
insights into molecular mechanisms of permeation and gating. Discuss.
2012 (Paper 1) Voltage-gated ion channel complexes comprise regulatory subunits/proteins
in addition to pore-forming subunits. Describe the experimental basis for our understanding
of their role in determining the properties of these channels within the nervous system.
2012 (Paper 2) Discuss advances in our understanding of potassium channel gating and
permeation contributed by the solving of their crystal structures.
2011 (Paper 1) Neuronal voltage-gated ion channels are subject to regulation by protein-
protein interactions and second messengers. How is this important for neuronal activity?
2011 (Paper 2) Critically evaluate the experimental basis for our understanding of voltage-
dependent ion channel gating.
2010 (Paper 1) Discuss mechanisms by which the distribution and function of voltage gated
ion channels are regulated by factors other than voltage.
,2010 (Paper 2) Critically evaluate the evidence contributing to our current understanding
of the molecular mechanisms involved in the gating and permeation of voltage gated
potassium channels
2009 (Paper 2) How has X-ray crystallography contributed to our understanding of voltage-
gated ion channels?
2008 (Paper 1) How do potassium channels achieve very high rates of ion permeation
combined with high selectivity?
Introduction
• Ion channels are ubiquitous across domains and kingdoms and maintained conserved
structural features in spite of thousands of years of divergent evolution.
• Homologues are found among prokaryotes and eukaryotes.
• Investigating bacterial counterparts has historically given an insight into the structure-
function relationship for ion channels of more complex organisms, in particular, human ion
channels.
• More functional studies are carried out on mammalian ion channels while more structural
studies are conducted on bacterial ion channels while functional characterisation surprisingly
lags behind.
• The cytoplasmic membranes in unicellular organisms play an essential role in energy
transduction, which is proposed to be the main physiological function of ion channels but yet
many conundrums remain – why unicellular organisms have more ion channel genes than
humans and why ion channels in bacteria evolved to be ion selective if only the charge
balance matters?
• Voltage-gated ion channels are a class of transmembrane proteins that form ion channels
that are activated by changes in the electrical membrane potential near the channel. These
electrical changes alter the conformation of the channels and cause opening and closure,
which controls ion flux across the membrane as the membranes are generally impermeable
to charged moieties and act as insulators.
• In animals, they play a critical role in excitable cells, e.g. neuronal and muscle tissues, where
they coordinate rapid depolarisation in response to voltage changes. They are characterized
by conserved rapid kinetics because mostly required for signal transduction on ms timescale.
• However, they have been also identified in many non-excitable cells and appear to play
emerging roles in intercellular signaling, implicated in various pathologies, e.g. in cancer.
What are the key foundational papers in ion channel research?
1902, Bernstein, Membrane Theory of Electric Potentials:
- proposed that excitable cells are surrounded by a membrane that is selectively
permeable to K+ ions at rest and during excitation permeable to other ions
1940s, Hodgkin & Huxley, Model of Action Potential in the Squid Giant Axon:
- characterized action potential as coordinated changes in membrane permeability to
Na+ and K+ and established a correlation between fluxes of ions across the
membranes with excitation and electrical conduction
,What is the function of voltage-gated ion channels in excitable cells?
- To conduct signals along the cells via changes in membrane potential by closing and
opening of channels
Which channels are responsible for fast action potential generation?
- Nav in nerve conduction
What channels are responsible for slow action potential generation?
- Cav in muscle cells and neurons
How is resting state maintained in excitable cells?
- by K+ efflux via K+ voltage-gated channels
How are depolarisation and repolarisation brought about?
- The excitable cell is depolarised - membrane potential changes from -ve to +ve mV -
due to the influx of Na+ and Ca2+ via Nav and Cav channels.
- The excitable cell is repolarised - membrane potential recovers from +ve to -ve mV -
due to K+ efflux via Kv channels.
Ion Balance of a Resting Cell
Main transport mechanisms to maintain ionic gradients:
1) ATP-depenednt Na+/K+ pump
2) Ca+ pump
3) Na+/Ca2+ exchange transporter
- The resting membrane potential is around -60-70 mV but differs for different cell
types, determined by the equilibrium potentials of ion channels involved.
- At rest, the membrane is relatively permeable to K+ (vg channels are open) but
impermeable to other cations.
- Only cation exchange shown in the diagram for simplicity.
, - The value of resting potential is determined by the dynamic equilibrium between the
ion flow through the channels (permeability of the membrane) and active ion
transport (efficiency of the ion pumps).
What is an equilibrium potential?
- An equilibrium potential (also known as reversal potential) is the membrane
potential where the net flow through any open channels is zero. May be calculated
for a neuron using the Nernst equation.
- In mammalian neurons, the equilibrium potential for Na+ is ~-60 mV, for K+ is ~-88
mV and for Cl- is 70 mV.
Which 2 factors determine the direction of ion movement across the membrane?
1) electrical potential difference - if membrane potential is +ve, +ve ions will move
outside, if membrane potential is -ve, +ve ions will move inside and vice versa for if
memrbane potential is -ve - if voltage is @ 0 mV, electrical potential difference will
have no effect on ion transport
2) concentration gradient - ions will move from higher to lower concentrations across
the open ion channels
Examples of excitable cells
- neurons
- muscle cells - skeletal, cardiac and smooth
- retinal glial cells
- lymphocytes
- insulin-releasing pancreatic beta-cells (example of endocrine cells)
Gating:
- Activation
o opening of the activation gate
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