A role for TASK2 channels in the human immunological synapse.

The immunological synapse is a transient junction that occurs when the plasma membrane of a T cell comes in close contact with an APC after recognizing a peptide from the antigen-MHC. The interaction starts when CRAC channels embedded in the T cell membrane open, flowing calcium ions into the cell. To counterbalance the ion influx and subsequent depolarization, Kv 1.3 and KCa3.1 channels are recruited to the immunological synapse, increasing the extracellular K+ concentration. These processes are crucial as they initiate gene expression that drives T cell activation and proliferation. The T cell-specific function of the K2P channel family member TASK2 channels and their role in autoimmune processes remains unclear. Using mass spectrometry analysis together with epifluorescence and super-resolution single-molecule localization microscopy, we identified TASK2 channels as novel players recruited to the immunological synapse upon stimulation. TASK2 localizes at the immunological synapse, upon stimulation with CD3 antibodies, likely interacting with these molecules. Our findings suggest that, together with Kv 1.3 and KCa3.1 channels, TASK2 channels contribute to the proper functioning of the immunological synapse, and represent an interesting treatment target for T cell-mediated autoimmune disorders.

Reorganization of Brain Functional Network during Task Switching before and after Mental Fatigue.

Mental fatigue is a widely studied topic on account of its serious negative effects. But how the neural mechanism of task switching before and after mental fatigue remains a question. To this end, this study aims to use brain functional network features to explore the answer to this question. Specifically, task-state EEG signals were recorded from 20 participants. The tasks include a 400-s 2-back-task (2-BT), followed by a 6480-s of mental arithmetic task (MAT), and then a 400-s 2-BT. Network features and functional connections were extracted and analyzed based on the selected task switching states, referred to from Pre_2-BT to Pre_MAT before mental fatigue and from Post_MAT to Post_2-BT after mental fatigue. The results showed that mental fatigue has been successfully induced by long-term MAT based on the significant changes in network characteristics and the high classification accuracy of 98% obtained with Support Vector Machines (SVM) between Pre_2-BT and Post_2-BT. when the task switched from Pre_2-BT to Pre_MAT, delta and beta rhythms exhibited significant changes among all network features and the selected functional connections showed an enhanced trend. As for the task switched from Post_MAT to Post_2-BT, the network features and selected functional connectivity of beta rhythm were opposite to the trend of task switching before mental fatigue. Our findings provide new insights to understand the neural mechanism of the brain in the process of task switching and indicate that the network features and functional connections of beta rhythm can be used as neural markers for task switching before and after mental fatigue.

Contribution of retrotrapezoid nucleus neurons to CO2 -amplified cardiorespiratory activity in spontaneously hypertensive rats.

KEY POINTS: This study demonstrates that both CO2 -induced respiratory and cardiovascular responses are augmented in spontaneously hypertensive rats (SHRs). Genetic ablation of the retrotrapezoid nucleus (RTN) neurons depresses enhanced hypercapnic ventilatory response and eliminates CO2 -stimulated increase in arterial pressure and heart rate in SHRs. SHRs have a high protein level of pH-sensitive channels in the RTN, including the TASK-2 channel, Kv12.1 channel and acid-sensing ion channel 3. The inhibition of putative TASK-2 channel activity by clofilium diminishes amplified hypercapnic ventilatory and cardiovascular responses, and reduces the number of CO2 -activated RTN neurons in SHRs. These results indicate that RTN neurons contribute to enhanced CO2 -stimulated respiratory and cardiovascular responses in SHRs. ABSTRACT: The respiratory regulation of cardiovascular activity is essential for maintaining an efficient ventilation and perfusion ratio. Activation of central respiratory chemoreceptors not only elicits a ventilatory response but also regulates sympathetic nerve activity and arterial blood pressure (ABP). The retrotrapezoid nucleus (RTN) is the most completely characterized cluster of central respiratory chemoreceptors. We hypothesize that RTN neurons contribute to augmented CO2 -stimulated respiratory and cardiovascular responses in adult spontaneously hypertensive rats (SHRs). Our findings indicate that SHRs exhibit more enhanced hypercapnic cardiorespiratory responses than age-matched normotensive Wistar-Kyoto rats. Genetic ablation of RTN neurons notably depresses an enhanced hypercapnic ventilatory response (HCVR) and eliminates a CO2 -stimulated greater increase in ABP and heart rate in SHRs. In addition, SHRs have a higher protein level of pH-sensitive channels in the RTN, including TASK-2 channels, Kv12.1 channels and acid-sensing ion channel 3. Administration of clofilium (i.p.), an unselective inhibitor of TASK-2 channels, not only significantly reduces the enhanced HCVR but also inhibits CO2 -amplified increases in ABP and heart rate in SHRs. Moreover, clofilium significantly decreases the number of CO2 -activated RTN neurons in SHRs. Taken together, we suggest that RTN neurons play an important role in enhanced hypercapnic ventilatory and cardiovascular responses in SHRs and the putative mechanism involved is associated with TASK-2 channel activity in the RTN.

The role of TASK-2 channels in CO2 sensing in zebrafish (Danio rerio).

Peripheral chemosensitivity in fishes is thought to be mediated by serotonin-enriched neuroepithelial cells (NECs) that are localized to the gills of adults and the integument of larvae. In adult zebrafish (Danio rerio), branchial NECs are presumed to mediate the cardiorespiratory reflexes associated with hypoxia or hypercapnia, whereas in larvae, there is indirect evidence linking cutaneous NECs to hypoxic hyperventilation and hypercapnic tachycardia. No study yet has examined the ventilatory response of larval zebrafish to hypercapnia, and regardless of developmental stage, the signaling pathways involved in CO2 sensing remain unclear. In the mouse, a background potassium channel (TASK-2) contributes to the sensitivity of chemoreceptor cells to CO2. Zebrafish possess two TASK-2 channel paralogs, TASK-2 and TASK-2b, encoded by kcnk5a and kcnk5b, respectively. The present study aimed to determine whether TASK-2 channels are expressed in NECs of larval zebrafish and whether they are involved in CO2 sensing. Using immunohistochemical approaches, TASK-2 protein was observed on the surface of NECs in larvae. Exposure of larvae to hypercapnia caused cardiac and breathing frequencies to increase, and these responses were blunted in fish experiencing TASK-2 and/or TASK-2b knockdown. The results of these experiments suggest that TASK-2 channels are involved in CO2 sensing by NECs and contribute to the initiation of reflex cardiorespiratory responses during exposure of larvae to hypercapnia.

Elucidating the Structural Basis of the Intracellular pH Sensing Mechanism of TASK-2 K2P Channels.

Two-pore domain potassium (K2P) channels maintain the cell's background conductance by stabilizing the resting membrane potential. They assemble as dimers possessing four transmembrane helices in each subunit. K2P channels were crystallized in "up" and "down" states. The movements of the pore-lining transmembrane TM4 helix produce the aperture or closure of side fenestrations that connect the lipid membrane with the central cavity. When the TM4 helix is in the up-state, the fenestrations are closed, while they are open in the down-state. It is thought that the fenestration states are related to the activity of K2P channels and the opening of the channels preferentially occurs from the up-state. TASK-2, a member of the TALK subfamily of K2P channels, is opened by intracellular alkalization leading the deprotonation of the K245 residue at the end of the TM4 helix. This charge neutralization of K245 could be sensitive or coupled to the fenestration state. Here, we describe the relationship between the states of the intramembrane fenestrations and K245 residue in TASK-2 channel. By using molecular modeling and simulations, we show that the protonated state of K245 (K245+) favors the open fenestration state and, symmetrically, that the open fenestration state favors the protonated state of the lysine residue. We show that the channel can be completely blocked by Prozac, which is known to induce fenestration opening in TREK-2. K245 protonation and fenestration aperture have an additive effect on the conductance of the channel. The opening of the fenestrations with K245+ increases the entrance of lipids into the selectivity filter, blocking the channel. At the same time, the protonation of K245 introduces electrostatic potential energy barriers to ion entrance. We computed the free energy profiles of ion penetration into the channel in different fenestration and K245 protonation states, to show that the effects of the two transformations are summed up, leading to maximum channel blocking. Estimated rates of ion transport are in qualitative agreement with experimental results and support the hypothesis that the most important barrier for ion transport under K245+ and open fenestration conditions is the entrance of the ions into the channel.

Neuromedin B Expression Defines the Mouse Retrotrapezoid Nucleus.

The retrotrapezoid nucleus (RTN) consists, by definition, of Phox2b-expressing, glutamatergic, non-catecholaminergic, noncholinergic neurons located in the parafacial region of the medulla oblongata. An unknown proportion of RTN neurons are central respiratory chemoreceptors and there is mounting evidence for biochemical diversity among these cells. Here, we used multiplexed in situ hybridization and single-cell RNA-Seq in male and female mice to provide a more comprehensive view of the phenotypic diversity of RTN neurons. We now demonstrate that the RTN of mice can be identified with a single and specific marker, Neuromedin B mRNA (Nmb). Most (∼75%) RTN neurons express low-to-moderate levels of Nmb and display chemoreceptor properties. Namely they are activated by hypercapnia, but not by hypoxia, and express proton sensors, TASK-2 and Gpr4. These Nmb-low RTN neurons also express varying levels of transcripts for Gal, Penk, and Adcyap1, and receptors for substance P, orexin, serotonin, and ATP. A subset of RTN neurons (∼20-25%), typically larger than average, express very high levels of Nmb mRNA. These Nmb-high RTN neurons do not express Fos after hypercapnia and have low-to-undetectable levels of Kcnk5 or Gpr4 transcripts; they also express Adcyap1, but are essentially devoid of Penk and Gal transcripts. In male rats, Nmb is also a marker of the RTN but, unlike in mice, this gene is expressed by other types of nearby neurons located within the ventromedial medulla. In sum, Nmb is a selective marker of the RTN in rodents; Nmb-low neurons, the vast majority, are central respiratory chemoreceptors, whereas Nmb-high neurons likely have other functions.SIGNIFICANCE STATEMENT Central respiratory chemoreceptors regulate arterial PCO2 by adjusting lung ventilation. Such cells have recently been identified within the retrotrapezoid nucleus (RTN), a brainstem nucleus defined by genetic lineage and a cumbersome combination of markers. Using single-cell RNA-Seq and multiplexed in situ hybridization, we show here that a single marker, Neuromedin B mRNA (Nmb), identifies RTN neurons in rodents. We also suggest that >75% of these Nmb neurons are chemoreceptors because they are strongly activated by hypercapnia and express high levels of proton sensors (Kcnk5 and Gpr4). The other RTN neurons express very high levels of Nmb, but low levels of Kcnk5/Gpr4/pre-pro-galanin/pre-pro-enkephalin, and do not respond to hypercapnia. Their function is unknown.

The potassium channels TASK2 and TREK1 regulate functional differentiation of murine skeletal muscle cells.

Two-pore domain potassium (K2P) channels influence basic cellular parameters such as resting membrane potential, cellular excitability, or intracellular Ca2+-concentration [Ca2+]i While the physiological importance of K2P channels in different organ systems (e.g., heart, central nervous system, or immune system) has become increasingly clear over the last decade, their expression profile and functional role in skeletal muscle cells (SkMC) remain largely unknown. The mouse SkMC cell line C2C12, wild-type mouse muscle tissue, and primary mouse muscle cells (PMMs) were analyzed using quantitative PCR, Western blotting, and immunohistochemical stainings as well as functional analysis including patch-clamp measurements and Ca2+ imaging. Mouse SkMC express TWIK-related acid-sensitive K+ channel (TASK) 2, TWIK-related K+ channel (TREK) 1, TREK2, and TWIK-related arachidonic acid stimulated K+ channel (TRAAK). Except TASK2 all mentioned channels were upregulated in vitro during differentiation from myoblasts to myotubes. TASK2 and TREK1 were also functionally expressed and upregulated in PMMs isolated from mouse muscle tissue. Inhibition of TASK2 and TREK1 during differentiation revealed a morphological impairment of myoblast fusion accompanied by a downregulation of maturation markers. TASK2 and TREK1 blockade led to a decreased K+ outward current and a decrease of ACh-dependent Ca2+ influx in C2C12 cells as potential underlying mechanisms. K2P-channel expression was also detected in human muscle tissue by immunohistochemistry pointing towards possible relevance for human muscle cell maturation and function. In conclusion, our findings for the first time demonstrate the functional expression of TASK2 and TREK1 in muscle cells with implications for differentiation processes warranting further investigations in physiologic and pathophysiologic scenarios.

The two-pore domain K2 P channel TASK2 drives human NK-cell proliferation and cytolytic function.

Natural killer (NK) cells are a subset of cytotoxic lymphocytes that recognize and kill tumor- and virus-infected cells without prior stimulation. Killing of target cells is a multistep process including adhesion to target cells, formation of an immunological synapse, and polarization and release of cytolytic granules. The role of distinct potassium channels in this orchestrated process is still poorly understood. The current study reveals that in addition to the voltage-gated KV 1.3 and the calcium-activated KCa 3.1 channels, human NK cells also express the two-pore domain K2 P channel TASK2 (TWIK-related acid-sensitive potassium channel). Expression of Task2 varies among NK-cell subsets and depends on their differentiation and activation state. Despite its different expression in TASK2(high) CD56(bright) CD16(-) and TASK2(low) CD56(dim) CD16(+) NK cells, TASK2 is involved in cytokine-induced proliferation and cytolytic function of both subsets. TASK2 is crucial for leukocyte functional antigen (LFA-1) mediated adhesion of both resting and cytokine-activated NK cells to target cells, an early step in killing of target cells. With regard to the following mechanism, TASK2 plays a role in release of cytotoxic granules by resting, but not IL-15-induced NK cells. Taken together, our data exhibit two-pore potassium channels as important players in NK-cell activation and effector function.

Myometrial relaxation of mice via expression of two pore domain acid sensitive K(+) (TASK-2) channels.

Myometrial relaxation of mouse via expression of two-pore domain acid sensitive (TASK) channels was studied. In our previous report, we suggested that two-pore domain acid-sensing K(+) channels (TASK-2) might be one of the candidates for the regulation of uterine circular smooth muscles in mice. In this study, we tried to show the mechanisms of relaxation via TASK-2 channels in marine myometrium. Isometric contraction measurements and patch clamp technique were used to verify TASK conductance in murine myometrium. Western blot and immunehistochemical study under confocal microscopy were used to investigate molecular identity of TASK channel. In this study, we showed that TEA and 4-AP insensitive non-inactivating outward K(+) current (NIOK) may be responsible for the quiescence of murine pregnant longitudinal myometrium. The characteristics of NIOK coincided with two-pore domain acid-sensing K(+) channels (TASK-2). NIOK in the presence of K(+) channel blockers was inhibited further by TASK inhibitors such as quinidine, bupivacaine, lidocaine, and extracellular acidosis. Furthermore, oxytocin and estrogen inhibited NIOK in pregnant myometrium. When compared to non-pregnant myometrium, pregnant myometrium showed stronger inhibition of NIOK by quinidine and increased immunohistochemical expression of TASK-2. Finally, TASK-2 inhibitors induced strong myometrial contraction even in the presence of L-methionine, a known inhibitor of stretch-activated channels in the longitudinal myometrium of mouse. Activation of TASK-2 channels seems to play an essential role for relaxing uterus during pregnancy and it might be one of the alternatives for preventing preterm delivery.

Murine K2P5.1 Deficiency Has No Impact on Autoimmune Neuroinflammation due to Compensatory K2P3.1- and KV1.3-Dependent Mechanisms.

Lymphocytes express potassium channels that regulate physiological cell functions, such as activation, proliferation and migration. Expression levels of K2P5.1 (TASK2; KCNK5) channels belonging to the family of two-pore domain potassium channels have previously been correlated to the activity of autoreactive T lymphocytes in patients with multiple sclerosis and rheumatoid arthritis. In humans, K2P5.1 channels are upregulated upon T cell stimulation and influence T cell effector functions. However, a further clinical translation of targeting K2P5.1 is currently hampered by a lack of highly selective inhibitors, making it necessary to evaluate the impact of KCNK5 in established preclinical animal disease models. We here demonstrate that K2P5.1 knockout (K2P5.1-/-) mice display no significant alterations concerning T cell cytokine production, proliferation rates, surface marker molecules or signaling pathways. In an experimental model of autoimmune neuroinflammation, K2P5.1-/- mice show a comparable disease course to wild-type animals and no major changes in the peripheral immune system or CNS compartment. A compensatory upregulation of the potassium channels K2P3.1 and KV1.3 seems to counterbalance the deletion of K2P5.1. As an alternative model mimicking autoimmune neuroinflammation, experimental autoimmune encephalomyelitis in the common marmoset has been proposed, especially for testing the efficacy of new potential drugs. Initial experiments show that K2P5.1 is functionally expressed on marmoset T lymphocytes, opening up the possibility for assessing future K2P5.1-targeting drugs.

Mechanism of Relaxation Via TASK-2 Channels in Uterine Circular Muscle of Mouse.

Plasma pH can be altered during pregnancy and at labor. Membrane excitability of smooth muscle including uterine muscle is suppressed by the activation of K(+) channels. Because contractility of uterine muscle is regulated by extracellular pH and humoral factors, K(+) conductance could be connected to factors regulating uterine contractility during pregnancy. Here, we showed that TASK-2 inhibitors such as quinidine, lidocaine, and extracellular acidosis produced contraction in uterine circular muscle of mouse. Furthermore, contractility was significantly increased in pregnant uterine circular muscle than that of non-pregnant muscle. These patterns were not changed even in the presence of tetraetylammonium (TEA) and 4-aminopyridine (4-AP). Finally, TASK-2 inhibitors induced strong myometrial contraction even in the presence of L-methionine, a known inhibitor of stretchactivated channels in myometrium. When compared to non-pregnant myometrium, pregnant myometrium showed increased immunohistochemical expression of TASK-2. Therefore, TASK-2, seems to play a key role during regulation of myometrial contractility in the pregnancy and provides new insight into preventing preterm delivery.

The effects of cognitive-motor training interventions on executive functions in older people: a systematic review and meta-analysis.

BACKGROUND: Ageing is associated with physical and cognitive decline, affecting independence and quality of life in older people. Recent studies show that in particular executive functions are important for daily-life function and mobility. This systematic review investigated the effectiveness of cognitive-motor training including exergaming on executive function (EF, set-shifting, working memory, inhibitory control) in healthy older people. METHODS: An electronic database search for randomised controlled trials (RCT), controlled clinical trials (CCT) and parallel group trials was performed using MEDLINE, EMBASE, and PsychINFO following PRISMA guidelines. Inclusion criteria were: (1) community-dwelling participants > 60 years without a medical condition or medical treatment, (2) reporting at least one cognitive-motor intervention while standing or walking, (3) use of dual-task interventions using traditional methods or modern technology to deliver a cognitive-motor task, (4) inclusion of at least one cognitive outcome. The PEDro scale was used for quality assessment. RESULTS: A total of 1557 studies were retrieved, of which 25 studies were included in this review. Eleven studies used a technology-based dual-task intervention, while 14 trials conducted a general cognitive-motor training. The age range of the cohort was 69 to 87 years. The interventions demonstrated positive effects on global cognitive function [mean difference 0.6, 95% CI 0.29-0.90] and inhibitory control [mean difference 0.61, 95% CI 0.28-0.94]. Effects were heterogeneous (I2 range: 60-95) and did not remain after a sensitivity analysis. Processing speed and dual-task costs also improved, but meta-analysis was not possible. CONCLUSION: Cognitive-motor and technology-based interventions had a positive impact on some cognitive functions. Dual-task interventions led to improvements of domains related global cognitive functions and inhibitory control. Likewise, technology-based exergame interventions improved functions related to processing speed, attentional and inhibitory control. Training interventions with a certain level of exercise load such as progression in difficulty and task specificity were more effective to gain task-related adaptations on cognitive functions.

Gi Protein Modulation of the Potassium Channel TASK-2 Mediates Vesicle Osmotic Swelling to Facilitate the Fusion of Aquaporin-2 Water Channel Containing Vesicles.

Vesicle fusion is a fundamental cell biological process similar from yeasts to humans. For secretory vesicles, swelling is considered a step required for the expulsion of intravesicular content. Here this concept is revisited providing evidence that it may instead represent a general mechanism. We report the first example that non-secretory vesicles, committed to insert the Aquaporin-2 water channel into the plasma membrane, swell and this phenomenon is required for fusion to plasma membrane. Through an interdisciplinary approach, using atomic force microscope (AFM), a fluorescence-based assay of vesicle volume changes and NMR spectroscopy to measure water self-diffusion coefficient, we provide evidence that Gi protein modulation of potassium channel TASK-2 localized in AQP2 vesicles, is required for vesicle swelling. Estimated intravesicular K⁺ concentration in AQP2 vesicles, as measured by inductively coupled plasma mass spectrometry, was 5.3 mM, demonstrating the existence of an inwardly K⁺ chemical gradient likely generating an osmotic gradient causing vesicle swelling upon TASK-2 gating. Of note, abrogation of K⁺ gradient significantly impaired fusion between vesicles and plasma membrane. We conclude that vesicle swelling is a potentially important prerequisite for vesicle fusion to the plasma membrane and may be required also for other non-secretory vesicles, depicting a general mechanism for vesicle fusion.

Differential modulation of TWIK-related K+ channel (TREK) and TWIK-related acid-sensitive K+ channel 2 (TASK2) activity by pyrazole compounds.

Pyrazole derivatives were originally suggested as selective blockers of the transient receptor potential cation 3 (TRPC3) and channel. In particular, pyr3 and 10 selectively inhibit TRPC3, whereas pyr2 (BTP2) and 6 inhibit ORAI1. However, their effects on background K+ channel activity have not been elucidated. In this study, the effects of BTP2, pyr3, pyr6, and pyr10 were studied on cloned human TWIK-related K+ channels (TREKs) and TWIK-related acid-sensitive K+ channel 2 (TASK-2) channels, which modulate Ca2+ signaling by controlling membrane potential, in HEK293T-overexpressing cells by using a whole-cell patch clamp technique. Pyr3 potently inhibited TREK-1 (ITREK1), TREK-2 (ITREK2), and TASK2 current (ITASK-2) with half-maximal inhibitory concentrations (IC50) of 0.89±0.27, 1.95±1.44, and 2.42±0.39µM, respectively. BTP2 slightly inhibited ITASK-2 (80.3±2.5% at 100µM). In contrast, pyr6 at 100µM potentiated ITREK1 and ITREK2 by approximately 2.6- and 3.6-fold compared to the control and inhibited ITASK2 (38.7±9.2%). Pyr10 showed a subtype-specific inhibition of ITREK1 but not ITREK2. It also inhibited ITASK2 (70.9±3.1% at 100µM). To the best of our knowledge, this study is the first to describe the differential modulation of TREKs and TASK2 channels by pyrazole derivatives, previously used as inhibitors of TRPC3 and ORAI1. Therefore, studies using these drugs should consider their modulation of other channels such as TREK and TASK-2.

Increased cortico-striatal connectivity during motor practice contributes to the consolidation of motor memory in writer's cramp patients.

Sensorimotor representations of movements are created in the sensorimotor network through repeated practice to support successful and effortless performance. Writer's cramp (WC) is a disorder acquired through extensive practice of finger movements, and it is likely associated with the abnormal acquisition of sensorimotor representations. We investigated (i) the activation and connectivity changes in the brain network supporting the acquisition of sensorimotor representations of finger sequences in patients with WC and (ii) the link between these changes and consolidation of motor performance 24 h after the initial practice. Twenty-two patients with WC and 22 age-matched healthy volunteers practiced a complex sequence with the right (pathological) hand during functional MRI recording. Speed and accuracy were measured immediately before and after practice (day 1) and 24 h after practice (day 2). The two groups reached equivalent motor performance on day 1 and day 2. During motor practice, patients with WC had (i) reduced hippocampal activation and hippocampal-striatal functional connectivity; and (ii) overactivation of premotor-striatal areas, whose connectivity correlated with motor performance after consolidation. These results suggest that patients with WC use alternative networks to reach equiperformance in the acquisition of new motor memories.

TASK-2: a K2P K(+) channel with complex regulation and diverse physiological functions.

TASK-2 (K2P5.1) is a two-pore domain K(+) channel belonging to the TALK subgroup of the K2P family of proteins. TASK-2 has been shown to be activated by extra- and intracellular alkalinization. Extra- and intracellular pH-sensors reside at arginine 224 and lysine 245 and might affect separate selectivity filter and inner gates respectively. TASK-2 is modulated by changes in cell volume and a regulation by direct G-protein interaction has also been proposed. Activation by extracellular alkalinization has been associated with a role of TASK-2 in kidney proximal tubule bicarbonate reabsorption, whilst intracellular pH-sensitivity might be the mechanism for its participation in central chemosensitive neurons. In addition to these functions TASK-2 has been proposed to play a part in apoptotic volume decrease in kidney cells and in volume regulation of glial cells and T-lymphocytes. TASK-2 is present in chondrocytes of hyaline cartilage, where it is proposed to play a central role in stabilizing the membrane potential. Additional sites of expression are dorsal root ganglion neurons, endocrine and exocrine pancreas and intestinal smooth muscle cells. TASK-2 has been associated with the regulation of proliferation of breast cancer cells and could become target for breast cancer therapeutics. Further work in native tissues and cells together with genetic modification will no doubt reveal the details of TASK-2 functions that we are only starting to suspect.

Molecular basis of potassium channels in pancreatic duct epithelial cells.

Potassium channels regulate excitability, epithelial ion transport, proliferation, and apoptosis. In pancreatic ducts, K(+) channels hyperpolarize the membrane potential and provide the driving force for anion secretion. This review focuses on the molecular candidates of functional K(+) channels in pancreatic duct cells, including KCNN4 (KCa 3.1), KCNMA1 (KCa 1.1), KCNQ1 (Kv 7.1), KCNH2 (Kv 11.1), KCNH5 (Kv 10.2), KCNT1 (KCa 4.1), KCNT2 (KCa 4.2), and KCNK5 (K 2P 5.1). We will give an overview of K(+) channels with respect to their electrophysiological and pharmacological characteristics and regulation, which we know from other cell types, preferably in epithelia, and, where known, their identification and functions in pancreatic ducts and in adenocarcinoma cells. We conclude by pointing out some outstanding questions and future directions in pancreatic K(+) channel research with respect to the physiology of secretion and pancreatic pathologies, including pancreatitis, cystic fibrosis, and cancer, in which the dysregulation or altered expression of K(+) channels may be of importance.