Background potassium (K) channels control the resting membrane potential and excitability of many mammalian neurons. They are modulated by a range of compounds, which include neurotransmitters and general anaesthetic agents. The two-pore domain K (2-PK) channel superfamily has been proposed to underlie these background K channels (Goldstein et al. 2001). As their name implies, the individual subunits of this superfamily have two pore regions in the amino acid sequence, which both contribute to the single pore of the functional channel. In mammals, each subunit consists of four putative transmembrane domains as opposed to six for KV channels or two for KIR channels. Currently there are known to be fourteen mammalian channels in this 2-PK channel superfamily.
We have been considering the functional properties of four of these 2-PK channels, TASK-1, TASK-2, TASK-3 and TREK-1. Our goal is to establish a functional fingerprint for each of these channels to help us to determine which of them are the most important contributors to the background currents recorded from particular native neurons. Interestingly, although these channels are open at all potentials, of the four, only TASK-1 channels show no voltage dependence of activation or inactivation. TASK-2 channels and TREK-1 channels both display voltage-dependent activation, while TASK-3 channels display both voltage-dependent activation then inactivation. We are investigating the mechanisms underlying these voltage-dependent components.
It has not been established whether 2-PK channels can form heterodimers in native neurons. This is an important general issue since many cells are proposed to express a number of different 2-PK channels (Talley et al. 2001). For example, TASK-1 and TASK-3 channels are both functionally expressed in cerebellar granule neurons (Han et al. 2002). Recent studies provide information on this issue that is equivocal, with evidence both for and against the formation of heterodimers of 2-PK channels (Karschin et al. 2001, Czirjak & Enyedi, 2002). We have created a fixed pair tandem heterodimer of TASK-1 and TASK-3. We have found that this fixed tandem expresses functionally and we have used it to help us to predict whether TASK-1 and TASK-3 channels do, in fact, form heterodimers in native neurons.
Our work is supported by the MRC and the BBSRC.