title: Identification of the muscarinic pathway underlying cessation of sleep-related burst activity in rat thalamocortical relay neurons.
abstract: Modulation of the standing outward current (I                         (SO)) by muscarinic acetylcholine (ACh) receptor (MAChR) stimulation is fundamental for the state-dependent change in activity mode of thalamocortical relay (TC) neurons. Here, we probe the contribution of MAChR subtypes, G proteins, phospholipase C (PLC), and two pore domain K(+) (K(2P)) channels to this signaling cascade. By the use of spadin and A293 as specific blockers, we identify TWIK-related K(+) (TREK)-1 channel as new targets and confirm TWIK-related acid-sensitve K(+) (TASK)-1 channels as known effectors of muscarinic signaling in TC neurons. These findings were confirmed using a high affinity blocker of TASK-3 and TREK-1, namely, tetrahexylammonium chloride. It was found that the effect of muscarinic stimulation was inhibited by M(1)AChR-(pirenzepine, MT-7) and M(3)AChR-specific (4-DAMP) antagonists, phosphoinositide-specific PLCβ (PI-PLC) inhibitors (U73122, ET-18-OCH(3)), but not the phosphatidylcholine-specific PLC (PC-PLC) blocker D609. By comparison, depleting guanosine-5'-triphosphate (GTP) in the intracellular milieu nearly completely abolished the effect of MAChR stimulation. The block of TASK and TREK channels was accompanied by a reduction of the muscarinic effect on I                         (SO). Current-clamp recordings revealed a membrane depolarization following MAChR stimulation, which was sufficient to switch TC neurons from burst to tonic firing under control conditions but not during block of M(1)AChR/M(3)AChR and in the absence of intracellular GTP. These findings point to a critical role of G proteins and PLC as well as TASK and TREK channels in the muscarinic modulation of thalamic activity modes.
authors.affiliation: Institut für Physiologie I, Westfälische Wilhelms-Universität, Robert-Koch-Str. 27a, 48149, Münster, Germany.
authors.forename: Pawan
authors.initials: P
authors.lastname: Bista
authors.forename: Sven G
authors.initials: SG
authors.lastname: Meuth
authors.forename: Tatyana
authors.initials: T
authors.lastname: Kanyshkova
authors.forename: Manuela
authors.initials: M
authors.lastname: Cerina
authors.forename: Matthias
authors.initials: M
authors.lastname: Pawlowski
authors.forename: Petra
authors.initials: P
authors.lastname: Ehling
authors.forename: Peter
authors.initials: P
authors.lastname: Landgraf
authors.forename: Marc
authors.initials: M
authors.lastname: Borsotto
authors.forename: Catherine
authors.initials: C
authors.lastname: Heurteaux
authors.forename: Hans-Christian
authors.initials: HC
authors.lastname: Pape
authors.forename: Thomas
authors.initials: T
authors.lastname: Baukrowitz
authors.forename: Thomas
authors.initials: T
authors.lastname: Budde
mesh_terms: D000200:Action Potentials / Q000187:drug effects / Q000502:physiology*; D000818:Animals; D059329:Cholinergic Neurons / Q000187:drug effects / Q000502:physiology*; D055724:Electrophysiological Phenomena / Q000187:drug effects / Q000502:physiology; D043802:GTP-Binding Protein alpha Subunits, Gq-G11 / Q000235:genetics; D015870:Gene Expression / Q000235:genetics; D006153:Guanosine Diphosphate / Q000031:analogs & derivatives / Q000494:pharmacology; D006160:Guanosine Triphosphate / Q000037:antagonists & inhibitors / Q000378:metabolism; D006863:Hydrogen-Ion Concentration; D020647:Lateral Thalamic Nuclei / Q000166:cytology / Q000502:physiology; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology; D009116:Muscarine / Q000494:pharmacology; D018721:Muscarinic Agonists / Q000494:pharmacology; D018727:Muscarinic Antagonists / Q000494:pharmacology; D009419:Nerve Tissue Proteins; D010095:Oxotremorine / Q000031:analogs & derivatives / Q000494:pharmacology; D018408:Patch-Clamp Techniques; D054799:Phospholipase C beta / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D024683:Potassium Channels, Tandem Pore Domain / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D051381:Rats; D020318:Rats, Long-Evans; D043643:Receptor, Muscarinic M1 / Q000819:agonists / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D043587:Receptor, Muscarinic M3 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D012890:Sleep / Q000502:physiology*; D013788:Thalamus / Q000166:cytology / Q000502:physiology*; D013873:Thionucleotides / Q000494:pharmacology
chemical_list: C407082:Kcnk9 protein, rat; D018721:Muscarinic Agonists; D018727:Muscarinic Antagonists; D009419:Nerve Tissue Proteins; D024683:Potassium Channels, Tandem Pore Domain; D043643:Receptor, Muscarinic M1; D043587:Receptor, Muscarinic M3; D013873:Thionucleotides; C103742:potassium channel protein TREK-1; D006153:Guanosine Diphosphate; C420132:potassium channel subfamily K member 3; D010095:Oxotremorine; C042743:oxotremorine M; C023427:guanosine 5'-O-(2-thiodiphosphate); D009116:Muscarine; D006160:Guanosine Triphosphate; D054799:Phospholipase C beta; D043802:GTP-Binding Protein alpha Subunits, Gq-G11
references.citation: J Biol Chem. 2002 May 17;277(20):17733-42
references.pmid: 11886861
references.citation: Proc Natl Acad Sci U S A. 2000 Mar 28;97(7):3614-8
references.pmid: 10725353
references.citation: Exp Transl Stroke Med. 2010 Jul 20;2(1):14
references.pmid: 20646278
references.citation: Pflugers Arch. 2008 Sep;456(6):1049-60
references.pmid: 18350314
references.citation: Nat Rev Neurosci. 2001 Mar;2(3):175-84
references.pmid: 11256078
references.citation: J Biol Chem. 2010 Sep 17;285(38):29295-304
references.pmid: 20605797
references.citation: Eur J Pharmacol. 2007 Oct 1;571(2-3):138-44
references.pmid: 17628524
references.citation: Proc Natl Acad Sci U S A. 2006 Feb 28;103(9):3422-7
references.pmid: 16492788
references.citation: Neuroscience. 2008 Feb 19;151(4):1154-72
references.pmid: 18222039
references.citation: Brain Res. 1986 Apr 23;371(2):314-8
references.pmid: 3008945
references.citation: J Pharmacol Exp Ther. 1990 Nov;255(2):756-68
references.pmid: 2147038
references.citation: Cancer Res. 1992 May 15;52(10):2835-40
references.pmid: 1316230
references.citation: Cell. 1992 Nov 27;71(5):765-76
references.pmid: 1330325
references.citation: Proc Natl Acad Sci U S A. 2009 Aug 25;106(34):14628-33
references.pmid: 19667202
references.citation: Neuropharmacology. 2012 Jan;62(1):278-88
references.pmid: 21807005
references.citation: J Pharmacol Exp Ther. 1990 May;253(2):688-97
references.pmid: 2338654
references.citation: J Neurophysiol. 2006 Sep;96(3):1517-29
references.pmid: 16760342
references.citation: Nat Rev Neurosci. 2007 Apr;8(4):251-61
references.pmid: 17375039
references.citation: Prog Neurobiol. 1992 Oct;39(4):337-88
references.pmid: 1354387
references.citation: J Neurosci. 2003 Jul 23;23(16):6460-9
references.pmid: 12878686
references.citation: Pflugers Arch. 2012 Jan;463(1):53-71
references.pmid: 21912835
references.citation: Toxicon. 2000 Jun;38(6):747-61
references.pmid: 10695963
references.citation: Neuron. 2000 Feb;25(2):399-410
references.pmid: 10719894
references.citation: Cardiovasc Res. 2007 Jul 1;75(1):59-68
references.pmid: 17389142
references.citation: J Physiol. 2005 Apr 1;564(Pt 1):117-29
references.pmid: 15677683
references.citation: Nature. 1980 Jan 3;283(5742):90-2
references.pmid: 7350532
references.citation: Physiol Rev. 2010 Apr;90(2):559-605
references.pmid: 20393194
references.citation: J Physiol. 2011 Jul 1;589(Pt 13):3149-62
references.pmid: 21540350
references.citation: EMBO J. 2003 Oct 15;22(20):5403-11
references.pmid: 14532113
references.citation: Neuropharmacology. 2011 Oct-Nov;61(5-6):918-23
references.pmid: 21740918
references.citation: Nat Neurosci. 2006 Sep;9(9):1134-41
references.pmid: 16906152
references.citation: Am J Physiol Cell Physiol. 2001 Aug;281(2):C700-8
references.pmid: 11443069
references.citation: J Neurochem. 2009 Jun;109(5):1193-202
references.pmid: 19457160
references.citation: Neuron. 2008 Jun 26;58(6):859-70
references.pmid: 18579077
references.citation: Neuropharmacology. 2004 Aug;47(2):295-303
references.pmid: 15223308
references.citation: J Neurosci. 2001 Oct 1;21(19):7491-505
references.pmid: 11567039
references.citation: Br J Pharmacol. 2005 Mar;144(6):821-9
references.pmid: 15685212
references.citation: Pflugers Arch. 2007 Oct;455(1):83-95
references.pmid: 17520276
references.citation: Physiol Rev. 2005 Oct;85(4):1159-204
references.pmid: 16183910
references.citation: Proc Natl Acad Sci U S A. 1999 Dec 21;96(26):15222-7
references.pmid: 10611366
references.citation: J Biol Chem. 2002 Feb 15;277(7):5426-32
references.pmid: 11733509
references.citation: Front Cell Neurosci. 2010 Oct 25;4:132
references.pmid: 21267426
references.citation: Pflugers Arch. 2008 Sep;456(6):1061-73
references.pmid: 18478257
references.citation: Mol Endocrinol. 2000 Jun;14(6):863-74
references.pmid: 10847588
references.citation: J Physiol. 2007 Jan 15;578(Pt 2):377-85
references.pmid: 17068099
references.citation: EMBO J. 2011 Aug 05;30(17):3607-19
references.pmid: 21822218
references.citation: J Pharmacol Exp Ther. 2007 Oct;323(1):39-48
references.pmid: 17622574
references.citation: Cell Biochem Biophys. 2007;47(2):209-56
references.pmid: 17652773
references.citation: EMBO J. 2005 Jan 12;24(1):44-53
references.pmid: 15577940
references.citation: Mol Pharmacol. 2006 Apr;69(4):1468-76
references.pmid: 16424077
references.citation: Neuroscience. 2001;103(4):899-919
references.pmid: 11301200
references.citation: J Physiol. 2000 Dec 1;529 Pt 2:321-31
references.pmid: 11101643
references.citation: PLoS Biol. 2010 Apr 13;8(4):e1000355
references.pmid: 20405001
references.citation: Eur J Pharmacol. 1989 Aug 3;166(3):459-66
references.pmid: 2806372
references.citation: J Physiol. 2006 May 1;572(Pt 3):639-57
references.pmid: 16513667
references.citation: Mol Pharmacol. 2007 Jun;71(6):1666-75
references.pmid: 17374744
references.citation: Pflugers Arch. 2007 Oct;455(1):97-103
references.pmid: 17384962