Peripheral and central thermoreceptors are involved in sensing ambient and body temperature, respectively. Specialized cold and warm receptors are present in dorsal root ganglion sensory ®bres as well as in the anterior/preoptic hypothalamus. The two-pore domain mechano-gated K + channel TREK-1 is highly expressed within these areas. Moreover, TREK-1 is opened gradually and reversibly by heat. A 10°C rise enhances TREK-1 current amplitude by~7-fold. Prostaglandin E2 and cAMP, which are strong sensitizers of peripheral and central thermoreceptors, reverse the thermal opening of TREK-1 via protein kinase A-mediated phosphorylation of Ser333. Expression of TREK-1 in peripheral sensory neurons as well as in central hypothalamic neurons makes this K + channel an ideal candidate as a physiological thermoreceptor.

Human TWIK‐1, which has been cloned recently, is a new structural type of weak inward rectifier K+ channel. Here we report the structural and functional properties of TREK‐1, a mammalian TWIK‐1‐related K+ channel. Despite a low amino acid identity between TWIK‐1 and TREK‐1 (approximately 28%), both channel proteins share the same overall structural arrangement consisting of two pore‐forming domains and four transmembrane segments (TMS). This structural similarity does not give rise to a functional analogy. K+ currents generated by TWIK‐1 are inwardly rectifying while K+ currents generated by TREK‐1 are outwardly rectifying. These channels have a conductance of 14 pS. TREK‐1 currents are insensitive to pharmacological agents that block TWIK‐1 activity such as quinine and quinidine. Extensive inhibitions of TREK‐1 activity are observed after activation of protein kinases A and C. TREK‐1 currents are sensitive to extracellular K+ and Na+. TREK‐1 mRNA is expressed in most tissues and is particularly abundant in the lung and in the brain. Its localization in this latter tissue has been studied by in situ hybridization. TREK‐1 expression is high in the olfactory bulb, hippocampus and cerebellum. These results provide the first evidence for the existence of a K+ channel family with four TMS and two pore domains in the nervous system of mammals. They also show that different members in this structural family can have totally different functional properties.

A complementary DNA encoding a novel K ؉ channel, called TASK-2, was isolated from human kidney and its gene was mapped to chromosome 6p21. TASK-2 has a low sequence similarity to other two pore domain K ؉ channels, such as TWIK-1, TREK-1, TASK-1, and TRAAK (18 -22% of amino acid identity), but a similar topology consisting of four potential membrane-spanning domains. In transfected cells, TASK-2 produces noninactivating, outwardly rectifying K ؉ currents with activation potential thresholds that closely follow the K ؉ equilibrium potential. As for the related TASK-1 and TRAAK channels, the outward rectification is lost at high external K ؉ concentration. The conductance of TASK-2 was estimated to be 14.5 picosiemens in physiological conditions and 59.9 picosiemens in symmetrical conditions with 155 mM K ؉ . TASK-2 currents are blocked by quinine (IC 50 ‫؍‬ 22 M) and quinidine (65% of inhibition at 100 M) but not by the other classical K ؉ channel blockers tetraethylammonium, 4-aminopyridine, and Cs ؉ . They are only slightly sensitive to Ba 2؉ , with less than 17% of inhibition at 1 mM. As TASK-1, TASK-2 is highly sensitive to external pH in the physiological range. 10% of the maximum current was recorded at pH 6.5 and 90% at pH 8.8. Unlike all other cloned channels with two pore-forming domains, TASK-2 is essentially absent in the brain. In human and mouse, TASK-2 is mainly expressed in the kidney, where in situ hybridization shows that it is localized in cortical distal tubules and collecting ducts. This localization, as well as its functional properties, suggest that TASK-2 could play an important role in renal K ؉ transport.