Molecular basis of drug action: Ion-channels
There are four identified types of ion-channel through which calcium, potassium, sodium or chloride ions selectively pass. There are also some promiscuous channels which allow any cation to pass through. The pharmacological properties of all of these channels remains to be fully established. Limited information on calcium and potassium channels is outlined below.
(a) Voltage-dependent calcium channels
- Large unit conductance (25pS). Activated by high membrane potentials. Inactivated slowly by Ca2+-dependent/voltage-dependent mechanisms. Predominant type in muscle cells; mediate contraction in cardiac and smooth muscle cells. Activated by Bay K-8644, CGP 28392. Blocked by verapamil, dihydropyridines, diltiazem.
- Intermediate unit conductance (12-20pS). Activated by high membrane potentials. Inactivated at membrane potentials more positive than -40mV. Mainly neuronal; control neurotransmitter release. Blocked by w-conotoxin.
- Intermediate unit conductance (10-12pS). Activated at moderately high membrane potentials. Inactivated very slowly at membrane potentials more positive than -40 mV. Mainly neuronal: control neurotransmitter release (with N-type). Blocked by funnel web spider toxin w-aga-IVA.
- Small unit conductance (8pS). Activated at relatively negative membrane potentials. Transient Ca2+ current. Determine frequency of action potential generation in neurones and cardiac muscle cells.
Catterall, W.A. and Striessnig, J. (1992) Trends Pharmacol. Sci. 13, 256-262.
Spedding, M. and Paoletti, R. (1992) Pharmacol. Revs. 44, 363-376.
(b) Receptor-operated calcium channels
Receptor activation, rather than membrane potential, is the main trigger for opening these channels. See Barnard, E.A. (1992), Trends Biochem. Sci. 17, 368-374.
(c) Intracellularly-activated Ca2+-selective channels
- Ca2+ release channels in the sarcoplasmic reticulum, which release calcium for smooth muscle contraction (sometimes called ryanodine receptors, since this compound can activate them)
- Inositol-1,4,5-triphosphate (IP3) receptors. Activated by elevated intracellular levels of IP3 following stimulation of cell surface receptors. They are structurally similar to ryanodine receptors and also cause a release of intracellular calcium stores.
Taylor, C.W. and Marshall, I.C.B. (1992) Trends Biochem. Sci. 17, 403-407.
(a) Voltage-dependent potassium channels
Derived from a large gene family whose diversity of channel properties may arise from alternative splicing or post-translational modifications. These channels are associated with a number of well characterised currents: delayed rectifier, transient outward and inward rectifier.
(b) Calcium-activated potassium channels
Three currents have been associated with this type of potassium channel: the large, the intermediate and the small conductance currents.
(c) ATP-sensitive potassium channels
ATP has been found to inhibit the opening of some potassium channels through which the IK(ATP) current flows. Such channels are inward-rectifying and voltage dependent.
(d) Receptor-linked potassium channels
Some potassium channels are opened by muscarinic receptor activation through coupling to a G-protein. The M-current is associated with such channels.
For reviews on potassium channels see references below.
Jan, L.Y. & Jan, Y.N. (1992) Ann. Rev. Physiol., 54, 537-555.
Pongs, O. (1992) Trends. Pharmacol. Sci., 13, 359-365.
Sackin, H. & Giebisch, G. (1992) Ann. Rev. Physiol., 54, 81-96.
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