Ion channels
An ion channel is a protein
macromolecule that spans a biological membrane and allows ions to pass from one side of the membrane to the
other. The ions move in a direction determined by the electrochemical gradient
across the membrane. In general, ions will tend to flow from an area of high
concentration to one of low concentration. However, in the presence of a
voltage gradient it is possible for there to be no ion flow even with unequal
concentrations. The ion channel itself can be either open or closed. Opening
can be achieved either by changing the voltage across the membrane (e.g. a
depolarization or the arrival of an action potential) or by the binding of a
chemical substance to a receptor in or near the channel.
The two types of channel are called
voltage gated (or voltage sensitive) and chemically
activated (or ligand gated) channels, respectively. However, this
distinction is somewhat artificial as a number of voltage sensitive channels
can be modulated by neuro- transmitters as well as by Ca2+.
Furthermore, some ion channels are not opened by voltage changes or chemical messengers
but are directly opened by mechanical stretch or pressure (e.g. the somatosensory
and auditory receptors; see Chapters 23, 27, 31 and 32). The most important
property of ion channels is that they imbue the neurone with electrical
excitability (see Chapter 16) and while they are found in all parts of the
neurone, and to a lesser extent in neuroglial
cells, they are also seen in a host of non-neural cells.
All biological membranes, including
the neuronal membrane, are
composed of a lipid bilayer that has a high electrical resistance, i.e. ions will not readily flow through it.
Therefore, in order for ions to move across a membrane, it is necessary to have
either ‘pores’ (ion channels) in the lipid bilayer or ‘carriers’ that will
collect the ions from one side of the membrane and carry them across to the
other side where they are released. In neurones, the rate of ion transfer
necessary for signal transmission is too fast for any carrier system and so ion
channels (or ‘pores’) are employed by neurones for the transfer of ions across
the membrane.
The fundamental properties of an
ion channel are as follows:
•
It is
composed of a number of protein subunits that traverse the membrane and allow
ions to cross from one side to the other – a transmembrane pore.
•
The
channel so formed must be able to move from a closed to an open state
and back, although intermediate steps may be required.
•
It must be
able to open in response to specific stimuli. Most channels possess a sensor of
voltage change and so open in response to a depolarizing voltage, i.e. one that
moves the resting membrane potential from its resting value of approximately
−70 to −80 mV to a less negative value.
In contrast, some channels,
especially those found at synapses, are not opened by a voltage change but by a
chemical, e.g. acetyl- choline (ACh). These channels have a receptor for
that chemical and binding to this receptor leads to channel opening. However,
many channels possess both voltage and chemical sensors and the presence of an
intracellular ion or secondary messenger molecule (e.g. cyclic adenosine monophosphate [cAMP])
leads to a modulation of the ion flow across the membrane that the
voltage-dependent process has produced.
Activation of the voltage sensor or chemical receptor
leads to the opening of a ‘gate’ within the channel which allows ions to
flow through the channel. The channel is then closed by either a process of deactivation
(which is simply the reversal of the opening of the gate) or inactivation
which involves a second gate moving into the channel more slowly
than the activation gate moves out, so that there is a time when there is no
gate in the channel and ions can flow through it.
The flow of ions through the
channel can be either selective or non-selective. If the channel is selective
then it only allows certain ions through and it achieves this by means of a filter.
The selectivity filter is based on energetic considerations (thermodynamically)
and gives the channel its name, e.g. sodium channel. However, certain channels
are non-selective in that they allow many different types of similarly charged
ions through, e.g. ACh cation channel. The overall description of an ion
channel is in terms of a number of different physical measures. The net flow of
ions through a channel is termed
the current; while the conductance is defined as the reciprocal of resistance (current/voltage)
and represents the ease with which the ions can pass through the membrane. Permeability,
on the other hand, is defined as the rate of transport of a substance or ion
through the membrane for a given concentration difference.
There are many different types of
ion channel and even within a single family of ion-specific channels there are
multiple subtypes, e.g. there are
at least five different types of potassium channels. The number and type of ion
channel govern the response characteristics of the cell. In the case of
neurones, this is expressed in terms of the rate of action potential generation
and its response to synaptic inputs (see Chapters 15, 17, 45 and 61).
Clinical disorders of ion
channels
A number of pharmacological agents
work at the level of ion channels, including local anaesthetics and some
antiepileptic drugs. However, in recent years a number of neurological
disorders, primarily involving muscle, have been found to be caused by mutations
in the sodium and chloride ion channels. These conditions include various forms
of myotonia (delayed relaxation of skeletal muscle following
voluntary contraction, i.e. an inability to let go of objects easily) and
various forms of periodic paralyses in which patients develop a
transient flaccid weakness which can be either partial or generalized.
Furthermore, certain forms of
familial hemiplegic migraine (see Chapter 50) and cerebellar
dysfunction (see Chapter 40) are associated with abnormalities in the Ca2+
channel, and some forms of epilepsy (see Chapter 61) may be
caused by a disorder of specific ion channels. In other disorders there is a
redistribution or exposing of normally non-functioning ion channels. This
commonly occurs next to the node of Ranvier as a result of central demyelination
in multiple sclerosis and peripheral demyelination in the Guil-lain–Barré
syndrome, and results in an impairment in action potential propagation
(see Chapters 17 and 62). Finally, in some conditions, antibodies are produced
in the body (sometimes in response to a tumour) which react with voltage gated
ion channels, producing disorders in the central nervous system (e.g. limbic
encephalitis and anti-voltage gated potassium channels) as well as in
the peripheral nervous system (Lambert–Eaton myasthenic syndrome and
anti-voltage gated calcium channels).
