Chapter 4: Ion and Channels and Transporters
Ion Channels Underlying Action Potential
1. Based on ionic conductances and currents measured in voltage clamp
experiments, the postulated channels had to have several properties.
1. Because the ionic currents are quite large the channels had to be capable of
allowing ions to move across the membrane at high rates.
2. Because the currents depend on the electrochemical gradient across the
membrane, the channels had to make use of these gradients.
3. Because Na+ and K+ flow across the membrane independently of each other,
different channel types had to be capable of discriminating between Na+ and
K+, allowing only one of these ions to flow across the membrane under the
4. Finally, given that the ionic conductances are voltagedependent, the
channels had to be able to sense the voltage drop across the membrane
opening only when the voltage reached appropriate levels.
1. Highly speculative in the 1950s, later experimental work established beyond any
doubt that transmembrane proteins called voltagesensitive ion channels indeed
exist and are responsible for action potentials and all of the other electrical
2. The first direct evidence for the presence of voltagesensitive, ion selective
channels in nerve cell membranes came from measurements of the ionic currents
flowing through individual ion channels.
3. Patch clamping: an extraordinary sensitive voltage clamp method that permits
the measurement of ionic currents flowing through individual ion channels.
4. Microscopic currents: ionic currents flowing through single ion channels.
5. Macroscopic currents: ionic currents flowing through large numbers of ion
channels distributed over a substantial area of membrane.
6. Several observations further proved that the microscopic currents are due to the
opening of single voltageactivated Na+ channels.
1. The currents are carried by Na+; thus, they are directed inward when the
membrane potential is more negative than E , rNaerse the polarity at E arNa,
outward at more positive potentials, and are reduced in sixe when the Na+
concentration of the external medium is decreased.
1. This behaviour exactly parallels that of the macroscopic Na+ currents
2. This correspondence is difficult to appreciate in the measurement of
microscopic currents flowing through a single open channel, because
individual channels open an close in a random manner, as can be seen by
examining the individual traces.
3. Both the opening and closing of the channels are voltagedependent; thus the
channels are closed at 80mV but open when the membrane potential is
4. Tetrodotoxin, which blocks the macroscopic Na+ currents, also blocks
microscopic Na+ currents.
1. These results show that the microscopic Na+ current measured by
Hodgkin and Huxley does indeed arose from the aggregate effect of many thousands of microscopic Na+ currents, each representing the opening of
a single voltagesensitive Na+ channel.
7. Patch clamp experiments also revealed the properties of the channels responsible
for the macroscopic K+ currents associated with action potentials.
8. When the membrane potential is depolarized, microscopic outward currents can
be observed under conditions that block Na+ channels.
1. Thus, the microscopic currents like their macroscopic currents fail to
inactivate during brief depolarization.
1. The singlechannel currents are sensitive to ionic manipulations and
drugs that affect the macroscopic K+ currents and, like the macroscopic
K+ currents, are voltage dependent.
9. Ion selectivity: these channels are able to discriminate between Na+ and K+.
10. Voltage gated: term used to describe the ion channels whose opening and closing
is sensitive to membrane potential.
11. Voltage sensor: detects the potential across the membrane.
The Diversity of Ion Channels
12. Well over 100 ion channel genes have been discovered.
13. Channels genes can also be deleted from genetically tractable organisms, such as
mice or fruit flies, to determine the roles these channels play in the intact
14. Other channels, however, are gated by chemical signals that bind to extracellular
or intracellular domains on these proteins and are insensitive to membrane
15. Ion channel gene contains a large number of coding regions that can be spliced
together in different ways, giving rise to channel proteins that can have
dramatically different functional properties.
16. RNA encoding ion channels also can be edited, modifying their base composition
after transcription from the gene.
1. For example, editing the RNA encoding of some receptors for the
neurotransmitter glutamate changes a single amino acid within the receptor,
which in turn gives rise to channels that differ in their selectivity for cations
and in their conductance.
17. Channels are often made up of subunits encoded by different genes, with different
18. Channels are often made up of subunits encoded by different genes, with different
combinations of subunits producing channels of different functions.
1. Thus, although the basic electrical signals of the nervous system are relatively
stereotyped, the proteins responsible for generating these signals are
remarkable diverse, conferring specialized signalling properties to many of
the neuronal cell type that populate the nervous system.
VoltageGated Ion Channels 19. Voltagegated ion channels: are a class of transmembrane ion channels that are
activated by changes in electrical potential difference near the channel; these
types of ion channels are especially critical in neurons.
20. Many different genes have been discovered for each type of voltagegated
1. For example, the identification of 10 human Na+ channel. This finding was
unexpected because Na+ channels from many different cell types have similar
functional properties, consistent with their origin from a single gene.
21. SCN genes: Na+ channel genes.
22. CACNA genes: Ca+ channel genes.
23. The largest and most diverse class of voltagegated ion channels are the K+
24. Nearly 100 K+ channel genes are known; these fall into several distinct grouped
that differs substantially in their activation, gating, and inactivation properties.
25. Some take minutes to inactivate, as in the case of squid axon K+ channels. Other
inactivates within milliseconds, as is typical of most voltagegated Na+ channels.
26. These properties influence the duration and rate of action potential firing, with
important consequences for axonal conduction and synaptic transmission. Yet
ano2+er K+ channels respond to membrane hyperpolarization or to intracellular
27. Several types of voltage gated Cl channel have been identified. These channels
are present in every type of neuron, where they control excitability, help with
resting membrane potential, and help regulate cell volume
LigandGated Ion Channels
28. Ligandgated ion channels: Ion channels that respond to chemical signals
rather than to the changes in membrane potential generated by ionic gradients.
The term covers a large group of neurotransmitter receptors that combine
receptor and ion channel functions into a single molecule.
29. These channels are essential for synaptic transmission and other forms of cell
cell signalling phenomena,
1. Whereas the voltagegated ion channels underlying the action potential
typically allow only one type of ion to permeate, channels activated by
extracellular ligands are usually less selective, often allowing two or ore
types of ion to flow.
2. Other ligandgated channels are sensitive to chemical signals arising within
the cytoplasm of neurons, and can be selective for specific ions such as K+ or
Cl, or permeable to all physiological cations.
30. The main function of these channels is to convert intracellular chemical signals
into electrical information. This process is particularly important in s