Multiple ion channels influence neuronal excitability, and these are often subject to modulation by neurotransmitters. Prominent among these is a background or 'leak' K+ channel that is targeted for inhibition by neurotransmitters, leading to membrane depolarization and increased excitability. G protein-coupled receptors capable of mediating this effect have been identified for many transmitters (invariably those that couple via Gaq/l 1-family subunits), and whereas it represents a predominant mechanism for slow synaptic excitation throughout the brain, this phenomenon is particularly well described in motoneurons. Despite its widespread presence, the molecular identity of leak K+ channel(s) targeted for inhibition are unknown in most native systems, and the mechanisms of receptor-mediated channel inhibition remain obscure. A major goal of the current proposal is to identify the molecular substrate for a motoneuronal leak K about current. Evidence from our laboratory indicates that the two-pore domain K+ channel, TASK-1 (KCNK3), contributes to a pH- and neurotransmitter-sensitive leak K+ channel in hypoglossal motoneurons. New observations indicate that the closely related TASK-3 (KCNK9) subunit is also expressed in motoneurons. Moreover, preliminary data suggest that it may form heterodimers with TASK-1. We hypothesize that TASK-1 and TASK-3 form functional heterodimers that contribute to motoneuronal pH- and neurotransmitter-sensitive leak K+ currents. The second major goal is to characterize molecular mechanisms involved in receptor-mediated inhibition of these channels, focusing in turn on the molecules that represent the beginning (i.e., G proteins) and end points (TASK channels) of the receptor-activated signaling pathway. We hypothesize that Gag-family subunits provide the initial receptor-activated signal and that key determinants located in cytoplasmic domains of TASK channels are required for receptor-mediated TASK channel inhibition. For these studies, we utilize two experimental systems: a model system, based on heterologous expression of Gaq-coupled receptors and TASK channel subunits in mammalian cells, which recapitulates this modulatory mechanism; and a native neuronal system, in which heterologous gene expression is obtained in motoneurons using adenovirus vectors. The following Specific Aims are proposed: To determine if TASK channels can form functional heterodimers; To determine G protein subunits and channel domains involved in receptor-mediated TASK inhibition; and To determine contributions of TASK channels to motoneuronal currents and mechanisms of their modulation. These experiments will characterize molecular substrates underlying a native neurotransmitter-modulated leak K+ current and test key aspects of the mechanisms by which they are modulated.
| Zhang, Haopeng; Dong, Hailong; Cilz, Nicholas I et al. (2016) Neurotensinergic Excitation of Dentate Gyrus Granule Cells via G?q-Coupled Inhibition of TASK-3 Channels. Cereb Cortex 26:977-90 |
| Vu, Michael T; Du, Guizhi; Bayliss, Douglas A et al. (2015) TASK Channels on Basal Forebrain Cholinergic Neurons Modulate Electrocortical Signatures of Arousal by Histamine. J Neurosci 35:13555-67 |
| Morenilla-Palao, Cruz; Luis, Enoch; Fernández-Peña, Carlos et al. (2014) Ion channel profile of TRPM8 cold receptors reveals a role of TASK-3 potassium channels in thermosensation. Cell Rep 8:1571-82 |
| Lazarenko, Roman; Geisler, Jessica; Bayliss, Douglas et al. (2014) D-chiro-inositol glycan stimulates insulin secretion in pancreatic ? cells. Mol Cell Endocrinol 387:1-7 |
| Chiu, Yu-Hsin; Ravichandran, Kodi S; Bayliss, Douglas A (2014) Intrinsic properties and regulation of Pannexin 1 channel. Channels (Austin) 8:103-9 |
| Lohman, Alexander W; Weaver, Janelle L; Billaud, Marie et al. (2012) S-nitrosylation inhibits pannexin 1 channel function. J Biol Chem 287:39602-12 |
| Guagliardo, Nick A; Yao, Junlan; Hu, Changlong et al. (2012) TASK-3 channel deletion in mice recapitulates low-renin essential hypertension. Hypertension 59:999-1005 |
| Sandilos, Joanna K; Bayliss, Douglas A (2012) Physiological mechanisms for the modulation of pannexin 1 channel activity. J Physiol 590:6257-66 |
| Sandilos, Joanna K; Chiu, Yu-Hsin; Chekeni, Faraaz B et al. (2012) Pannexin 1, an ATP release channel, is activated by caspase cleavage of its pore-associated C-terminal autoinhibitory region. J Biol Chem 287:11303-11 |
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