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Journal of Physiology (2002), 542.2, p. 334
© Copyright 2002 The Physiological Society
DOI: 10.1113/jphysiol.2002.020008
Email: a.mathie{at}ic.ac.uk
Recently a group of potassium-selective pore-forming subunits with four transmembrane domains and two pore domains per subunit have been described (see Goldstein et al. 2001). These channels are expressed heterologously throughout the CNS. Often named two pore domain potassium (2PK) channels, it is these channels that are thought to underlie 'leak' K+ currents, open at all potentials. To date, 14 members of the mammalian 2PK family have been described. TWIK-1 (tandem of P domains in a weak-inward-rectifier K+ channel) was the first to be cloned and all subsequent channels have been named in relation to this one (Lesage & Lazdunski, 2000). They can be grouped, loosely, into five different subfamilies on the basis of structural and functional properties. These subfamilies are the TWIK family (TWIK-1, TWIK-2 and KCNK-7), the TASK family (TASK-1, TASK-3 and TASK-5) the TALK family (TALK-1, TASK-2 and TASK-4 (also called TALK-2)) the TREK family (TREK-1, TREK-2 and TRAAK) and the THIK family (THIK-1 and THIK-2).
The main functional differences between the different subfamilies of these channels reflect their differential regulation. So, for example, members of the TASK family of 2PK channels are highly sensitive to changes in extracellular pH, while those in the TREK family are enhanced by arachidonic acid and mechanical stretch. From a physiological perspective, a primary objective is to determine which cells possess which 2PK channels and whether they are important contributors to the background currents in these cells. In this regard, the most convincing evidence to date concerns TASK-1.
Cerebellar granule neurons (CGNs) possess a non-inactivating outward K+ current that is active at all membrane potentials. This current, termed IKSO (for standing-outward current), which has a major role in regulating the excitability of these cells, is openly rectifying and is inhibited by the activation of muscarinic acetylcholine receptors (Millar et al. 2000). IKSO is insensitive to the classical K+ channel blockers tetraethylammonium and 4-aminopyridine, but can be blocked by Ba2+, small extracellular acidification and the endocannabinoid, anandamide. It is enhanced by the volatile anaesthetic agent halothane. Inhibition of this current by muscarinic receptor activation or extracellular acidification increases granule cell excitability.
No fewer than 7 of the 14 2PK subunits are expressed in CGNs (see Talley et al. 2001). High levels of TASK-1, TASK-3, TREK-2, TWIK-1 and THIK-2 expression are found, whilst lower, but measurable levels of TREK-1 and TRAAK are also seen.
All of the functional properties of IKSO in whole-cell recordings correlate well with those of the 2PK channel TASK-1 (Millar et al. 2000). However, it is extremely difficult to distinguish the functional properties of TASK-1 channels from those of the more recently cloned TASK-3 channels at the whole-cell level. In this issue of the Journal of Physiology, Han et al. (2002) have taken the characterization of IKSO to another level by considering the detailed single channel properties of leak K+ currents in CGNs and comparing them with the single channel properties of cloned 2PKs in expression systems. The extra resolution afforded by such an approach has allowed Han et al. (2002) to show, convincingly, that the background K+ current in CGNs is much more complicated than previously envisaged. The striking correlation observed between the different single channel properties seen in CGNs and the properties of 2PK channels in expression systems suggests that three 2PK subunits (TASK-1, TASK-3 and TREK-2c) contribute to the background K+ current while a fourth, as yet unidentified K+ channel subunit, is also important. In immature granule cells this fourth channel and TASK-3 channels are dominant but, with development, the balance of power shifts to suggest that a combination of TASK-1, TASK-3 and, perhaps, TREK-2c channels are of primary importance.
An interesting question is whether TASK-1 and TASK-3 subunits function in isolation as homodimers or whether they have the potential to form heterodimers. Perhaps, by analogy with KCNQ channels, co-expression of two subunits might lead to a substantial increase in observed whole-cell current or else currents with properties distinct from either subunit alone. We, and others, have found that it is possible to construct functional mixed dimers of TASK-1 and TASK-3 channels. However, this does not address the question as to whether they can form in vivo. At present the available evidence is equivocal (see Karschin et al. 2001; Czirjak & Enyedi 2002). The single channel recordings of Han et al. (2002) shed some light on this issue. In the simplest scenario one might expect to observe single channel currents with properties (such as single channel conductance) intermediate between those seen for TASK-1 or TASK-3 homodimers. However, the recordings of Han et al. (2002) provide no evidence for the existence of such channels. What the work of Han et al. (2002) has shown is that, even in the absence of heterodimers, the correlation between expressed 2PK channel subunits and background K+ currents is more than a trivial task.
REFERENCES
CZIRJAK, G. & ENYEDI, P. (2002). Journal of Biological Chemistry 277, 5426-5432.
[Abstract/Full Text]
GOLDSTEIN, S.A.N., BOCKENHAUER, D., O'KELLY, I. & ZILBERBERG, N. (2001). Nature Reviews Neuroscience 2, 175-184.
[Medline]
HAN, J., TRUELL, J., GNATENCO, C. & KIM, D. (2002). Journal of Physiology 542, 431-444.
[Abstract/Full Text]
KARSCHIN, C., WISCHMEYER, E., PREISIG-MULLER, R., RAJAN, S., DERST, C., GRZESCHIK, K. -H., DAUT, J. & KARSCHIN, A. (2001). Molecular and Cellular Neuroscience 18, 632-648.
[Medline]
LESAGE, F. & LAZDUNSKI, M. (2000). American Journal of Physiology-Renal Physiology 279, F793-801.
MILLAR, J. A., BARRATT, L., SOUTHAN, A. P., PAGE, K. M., FYFFE, R. E. W., ROBERTSON, B. & MATHIE, A. (2000). Proceedings of the National Academy of Sciences of the USA 97, 3614-3618.
[Abstract/Full Text]
TALLEY, E. M., SOLORZANO, G., LEI, Q., KIM, D. & BAYLISS, D. A. (2001). Journal of Neuroscience 21, 7491-7505.
[Abstract/Full Text]
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