Identification of native rat cerebellar granule cell currents due to background K channel KCNK5 (TASK-2)
Department of Anesthesia and Perioperative Care, University of California, San Francisco, 513 Parnassus Ave., Room S-261, Box 0542, San Francisco, CA 94143, USA. Molecular Brain Research
(Impact Factor: 2).
10/2004; 128(2):112-20. DOI: 10.1016/j.molbrainres.2004.06.007
The TWIK-related, Acid Sensing K (TASK-2; KCNK5) potassium channel is a member of the tandem pore (2P) family of potassium channels and mediates an alkaline pH-activated, acid pH-inhibited, outward-rectified potassium conductance. In previous work, we demonstrated TASK-2 protein expression in newborn rat cerebellar granule neurons (CGNs). In this study, we demonstrate TASK-2 functional expression in CGNs as a component of the pH-sensitive, volatile anesthetic-potentiated, standing-outward potassium conductance (I(K,SO)). Using excised, inside-out patch-clamp technique, we studied CGNs grown in primary culture. We identified four distinct, noninactivating single channel potassium conductances, Types 1-4. Types 1-3 have previously been attributed to TASK-1 (KCNK3), TASK-3 (KCNK9) and TASK-1/TASK-3 heteromers, and TREK-2 (KCNK10) 2P potassium channel function, respectively; however, the Type 4 conductance is currently unassigned. Previous studies demonstrated that Type 4 single channel activity is potentiated by extracellular, alkaline pH and cytoplasmic arachidonic acid (10-20 microM) and inhibited by cytoplasmic tetraethylammonium (TEA; 1 mM). We determined that heterologously expressed TASK-2 channels have single channel gating, conductance properties and pH sensitivity identical to the Type 4 conductance. Additionally, we found that TASK-2 single channel activity, like the Type 4 conductance is potentiated by cytoplasmic arachidonic acid (20 microM) and inhibited by cytoplasmic TEA (1 mM). We conclude that TASK-2 mediates the Type 4 single channel conductance in CGNs as a component of I(K,SO).
Available from: Julio Morán
- "nnels has been reported in CGN : TWIK - 1 , THIK - 2 , TREK - 2 and KCNK - 7 , as high ; TRAAK , TWIK - 2 , TREK - 1 and KCNK - 5 , as low level of expression ( Gabriel et al . , 2002 ; Mathie et al . , 2003 ) . But only TREK - 2 and KCNK - 5 have been functionally characterized and contributed to about 10% and 40% of IKso current , respectively ( Cotten et al . , 2004 ; Han et al . , 2002 ) . 3 . 4 . Effect of organic compounds on the apoptotic cell death of CGN As previously mentioned the TASK channels seemed to be involved in K þ - dependent cell death of CGN ( Lauritzen et al . , 2003 ) . Since DPIs were IKso current inhibitors , it was manda - tory to evaluate their effect on these neurons in apo"
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ABSTRACT: TASK channels belong to the family of K(+) channels with 4 transmembrane segments and 2 pore domains (4TM/2P) per subunit. These channels have been related to apoptosis in cerebellar granule neurons (CGN), as well as cancer in other tissues. TASK current is regulated by hormones, neurotransmitters, anesthetics and divalent cations, which are not selective. Recently, there has been found some organic compounds that inhibit TASK current selectively. In order to find other modulators, we report here a group of five dihydropyrrolo[2,1-a]isoquinolines (DPIs), four of them with putative anticancer activity, that were evaluated on TASK-1 and TASK-3 channels. The compounds 1, 2 and 3 showed IC50 <320 μM on TASK-1 and TASK-3, intermediate activity on TASK-1/TASK-3 heterodimer, moderate effect over hslo and TREK-1 (500 μM), and practically not inhibition on Shaker-IR, herg and IRK2.1 potassium channels, when they were expressed heterologously in Xenopus laevis oocytes. In rat CGN, 500 μM of these three compounds induced a decrement by >39% of the TASK-carried leak current. Finally, only compound 1 showed significant protection (∼36%) against apoptotic death of CGN induced by K(+) deprivation. These results suggest that DPI compounds could be potential candidates for designing new selective inhibitors of TASK channels.
Available from: plosone.org
- "In CG cells, IK(SO), a muscarine sensitive resting membrane potassium current plays an important role in regulating excitability . Previous work has suggested that IK(SO) is most likely formed by K2P type channels, and may in fact be an amalgamation of several different K2P channel types , , , . "
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ABSTRACT: Dipeptidyl Peptidase-like Protein 6 (DPP6) is widely expressed in the brain where it co-assembles with Kv4 channels and KChIP auxiliary subunits to regulate the amplitude and functional properties of the somatodendritic A-current, ISA. Here we show that in cerebellar granule (CG) cells DPP6 also regulates resting membrane potential and input resistance by increasing the amplitude of the IK(SO) resting membrane current. Pharmacological analysis shows that DPP6 acts through the control of a channel with properties matching the K2P channel TASK-3. Heterologous expression and co-immunoprecipitation shows that DPP6 co-expression with TASK-3 results in the formation of a protein complex that enhances resting membrane potassium conductance. The co-regulation of resting and voltage-gated channels by DPP6 produces coordinate shifts in resting membrane potential and A-current gating that optimize the sensitivity of ISA inactivation gating to subthreshold fluctuations in resting membrane potential.
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ABSTRACT: Tandem pore domain (or 2P) K channels form a recently isolated family of channels that are responsible for background K currents in excitable tissues. Previous studies have indicated that 2P K channel activity produces membrane hyperpolarization, which may offer protection from cellular insults. To study the effect of these channels in neuroprotection, we overexpressed pH-sensitive 2P K channels by transfecting the partially transformed C8 cell line with these channels. Tandem pore weak inward rectifier K channel (TWIK)-related acid-sensitive K channel 3 (TASK-3, KCNK9) as well as other pH sensitive 2P K channels (TASK-1 and TASK-2) enhanced cell viability by inhibiting the activation of intracellular apoptosis pathways. To explore the cellular basis for this protection in a more complex cellular environment, we infected cultured hippocampal slices with Sindbis virus constructs containing the coding sequences of these channels. Expression of TASK-3 throughout the hippocampal structure afforded neurons within the dentate and CA1 regions significant protection from an oxygen-glucose deprivation (OGD) injury. Neuroprotection within TASK-3 expressing slices was also enhanced by incubation with isoflurane. These results confirm a protective physiologic capability of TASK-3 and related 2P K channels, and suggest agents that enhance their activity, such as volatile anesthetics may intensify these protective effects.
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