Cardiac ion channels
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There is a plethora of cardiac ion channels. Each has a specific function,
but all ion channels have critical feature in common.
The elegant Hodgkin-Huxley model {J Physiol Lond 1952 117 500-44}
still describes these fairly adequately - there are two gates
both of which have to be open for ions
to pass. In the resting state the "m" gate is closed and the "h" gate
is open. After the m gate has opened to allow ions to pass, the h gate
closes and this prevents further depolarisation until the h gate has
again opened. Recently we have become aware that substates occur, but
let us not confuse things too much!
Each ion channel has several subunits. In sodium and calcium channels, these
are covalently linked but the non-covalently linked potassium channel subunits
come in a variety of flavours, allowing for different mixes and thus a
variety of functional units. We have discovered various agents that
selectively block ion channels:
- Na channels are blocked by tetrodotoxin and lignocaine;
- Ca channels are blocked by dihydropyridines, benzothiapines, and
phenylalkylamines;
- K channels are blocked by a substantial array of drugs, including
many "antiarrhythmics" such as Vaughan Williams class III agents,
and also class IA and IC drugs.
The channels are also regulated by a variety of physiological mechanisms,
including:
- Phosphorylation by protein kinases;
- glycosylation;
The four alpha subunits (domains I..IV) making up the ion channel each have six transmembrane
regions, S 1 ..S 6 . S 5 and S 6 appear
to line the water-filled pore through which the ion moves, while S 4
seems to be an important voltage-sensitive element. The h gate is probably
identical to the cytoplasmic bridge between domain
III (S 6 ) and domain IV(S 1 ).
| Some potassium channels |
| Name | Abbreviation |
| Transient-outward | I to = I Kf |
| Outward-rectifying (delayed) | I K |
| calcium-activated | - |
| sodium-activated | - |
| ATP-sensitive | I K(ATP) |
| Acetylcholine-activated | I K(ACh) |
| Arachidonic acid-activated | - |
| Inward-rectifying | I K1 |
| cyclic-nucleotide gated channels | - |
At present we believe that three of the above are most important:
I to which opens early during repolarization, I K
which opens later on to finish off repolarisation, and I K1
which contributes to the resting membrane potential
[Curr Opin Anaesthes 1995 8 1-6pp].
Taking an evolutionary perspective, all channels appear to have come
from a primitive precursor. Two broad groups diverged early on - K +
and Ca ++ channels. Much later, the faster sodium channel appeared,
almost certainly as a refinement of the calcium channel. This fast channel
is vital for rapid communication between cells of complex multicellular
organisms! This doesn't mean that the slower calcium channels are unimportant
in the heart. Slow depolarization is vital for the normal function of the
sino-atrial and AV nodes, where rapid responses could result in an
electrical disaster (for example, if atrial fibrillation were rapidly
conducted to the ventricle, as may occur in some pathological circumstances,
resulting in unconsciousness and death). Thus calcium channels
mediate phase 0 depolarization in the SA and AV nodes.
The above list of potassium channels is incomplete: different combinations
of channels, and alternative splicing, may result in literally hundreds
of different variants! We know that K + channel variants account
for the QT prolongation and sudden death found in several hereditary
syndromes. Potassium channels not only control repolarization - they also
affect resting membrane potential, refractoriness and automaticity.
There are at least two broad classes of potassium channel:
- I to which activate and inactivate rapidly; and
- I K which are slower "delayed rectifier" channels.
These classes are readily identified by their response to inhibitors:
I to are 4-AminoPyridine sensitive, while I K respond
to tetraethylammonium. (The simplicity of this classification has been
mucked up by the discovery of I to2 channels, which is resistant
to the effect of 4AP, and sensitive to the presence of calcium ions).
There is considerable evidence that density of I to channels
varies between atria and ventricles, and even between subendocardial and
subepicardial ventricular cells.
Stimulation of acetylcholine receptors on the heart is known to slow
the heart. This probably occurs due to the opening of I K(ACh)
channels. The acetylcholine binds to m2 muscarinic receptors, resulting
in G protein stimulation which causes channel opening,
shown to occur in conducting tissue and even in human ventricular
myocytes!
The ischaemic myocardial cell with its low concentration of ATP
can partially compensate for energy lack by shortening action potential
duration. This shortening may be mediated by activation of
I K(ATP) channels when ATP levels drop, and is blocked by
tolbutamide.
The inward-rectifying potassium channel is an unusual modification of
the standard pattern - there are only two membrane-spanning segments,
and they lack a voltage-sensitive component. I K1 is important
in phase 3 repolarization. It is blocked by extracellular caesium and barium
ions. Several subunits have been cloned, including ROMK1 and IRK1.
The position of GIRK1 (=KGA) is unclear, as are BIR9..11. These names
have recently been superceded by the Kir1.x .. Kir5.x classification, just
to confusticate things even further. Aargh. GIRK (Kir3.x) probably
contributes to I K(ACh).
The nomenclature of various K + channel subunits is rather quaint:
- Shaker - fruit flies with abnormalities at this locus, well, shake!
Shaker is homologous to the alpha subunit of Na and Ca channels.
- Similar to Shaker are Shab, Shaw and Shal .
As usual, these have confusing synonyms: Kv1.x, Kv2.x, Kv3.x and
Kv4.x respectively.
- The eag gene is even more cute - it stands for ether-a-go-go which refers to the fact that fruit flies
with this mutant shake in response to ether anaesthesia! It
appears to contribute to cyclic-nucleotide gated potassium channels.
- h-erg , related to eag, is abnormal in LQT2, a form of
the long QT sydrome. The gene is on human chromosome 7.
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