title: Voltage sensitivity of M2 muscarinic receptors underlies the delayed rectifier-like activation of ACh-gated K(+) current by choline in feline atrial myocytes.
abstract: Choline (Ch) is a precursor and metabolite of the neurotransmitter acetylcholine (ACh). In canine and guinea pig atrial myocytes, Ch was shown to activate an outward K(+) current in a delayed rectifier fashion. This current has been suggested to modulate cardiac electrical activity and to play a role in atrial fibrillation pathophysiology. However, the exact nature and identity of this current has not been convincingly established. We recently described the unique ligand- and voltage-dependent properties of muscarinic activation of ACh-activated K(+) current (IKACh) and showed that, in contrast to ACh, pilocarpine induces a current with delayed rectifier-like properties with membrane depolarization. Here, we tested the hypothesis that Ch activates IKACh in feline atrial myocytes in a voltage-dependent manner similar to pilocarpine. Single-channel recordings, biophysical profiles, specific pharmacological inhibition and computational data indicate that the current activated by Ch is IKACh. Moreover, we show that membrane depolarization increases the potency and efficacy of IKACh activation by Ch and thus gives the appearance of a delayed rectifier activating K(+) current at depolarized potentials. Our findings support the emerging concept that IKACh modulation is both voltage- and ligand-specific and reinforce the importance of these properties in understanding cardiac physiology.
authors: E. G. Moreno-Galindo: C.U.I.B., Universidad de Colima, Av. 25 de Julio 965, Colonia Villa San Sebastián, C.P. 28045 Colima, Col., México. eloy@ucol.mx.
authors: Ricardo A
authors: RA
authors: Navarro-Polanco
authors: Iván A
authors: IA
authors: Aréchiga-Figueroa
authors: Pedro D
authors: PD
authors: Salazar-Fajardo
authors: Dora E
authors: DE
authors: Benavides-Haro
authors: Julio C
authors: JC
authors: Rodríguez-Elías
authors: Frank B
authors: FB
authors: Sachse
authors: Martin
authors: M
authors: Tristani-Firouzi
authors: José A
authors: JA
authors: Sánchez-Chapula
authors: Eloy G
authors: EG
authors: Moreno-Galindo
mesh_terms: D000200:Action Potentials; D000818:Animals; D002415:Cats; D002794:Choline / Q000494:pharmacology; D051668:Delayed Rectifier Potassium Channels / Q000378:metabolism*; D005260:Female; D006325:Heart Atria / Q000166:cytology / Q000378:metabolism*; D008297:Male; D008564:Membrane Potentials; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism* / Q000502:physiology; D010862:Pilocarpine / Q000494:pharmacology; D043585:Receptor, Muscarinic M2 / Q000378:metabolism*
chemical_list: D051668:Delayed Rectifier Potassium Channels; D043585:Receptor, Muscarinic M2; D010862:Pilocarpine; D002794:Choline
references: J Physiol. 2011 Apr 1;589(Pt 7):1741-53
references: 21282291
references: J Gen Physiol. 1996 May;107(5):611-9
references: 8740374
references: Physiol Rev. 2010 Jan;90(1):291-366
references: 20086079
references: Nature. 1985 Oct 10-16;317(6037):536-8
references: 2413367
references: Nature. 1985 Oct 10-16;317(6037):538-40
references: 2413368
references: Pflugers Arch. 1978 Nov 30;377(3):193-200
references: 569814
references: J Membr Biol. 1999 May 1;169(1):55-64
references: 10227852
references: J Pharmacol Exp Ther. 2000 Apr;293(1):196-205
references: 10734170
references: J Biol Chem. 2006 Aug 25;281(34):24204-15
references: 16760467
references: Pharmacol Rev. 1998 Jun;50(2):279-90
references: 9647869
references: J Cardiovasc Electrophysiol. 2002 May;13(5):465-74
references: 12030529
references: J Biol Chem. 2003 Jun 20;278(25):22482-91
references: 12684524
references: Auton Autacoid Pharmacol. 2007 Jan;27(1):1-11
references: 17199870
references: J Biol Chem. 2005 Jan 14;280(2):1490-8
references: 15528188
references: J Theor Biol. 1996 Aug 21;181(4):381-97
references: 8949584
references: Circ Res. 2001 Nov 23;89(11):1045-50
references: 11717162
references: Pflugers Arch. 2011 Aug;462(2):235-43
references: 21487692
references: Br J Pharmacol. 2000 Oct;131(3):569-77
references: 11015309
references: Am J Physiol. 1994 Jan;266(1 Pt 1):C42-51
references: 8304429
references: J Physiol. 1997 Feb 1;498 ( Pt 3):663-78
references: 9051578
references: J Physiol. 2009 Feb 15;587(Pt 4):713-9
references: 19218620
references: Expert Rev Mol Diagn. 2010 Mar;10(2):159-71
references: 20214535
references: Cell Physiol Biochem. 2005;16(4-6):163-74
references: 16301817
references: J Gen Physiol. 2010 Aug;136(2):203-24
references: 20660661
references: Pflugers Arch. 1982 Oct;395(1):6-18
references: 7177773
references: Pharmacol Rev. 1985 Mar;37(1):1-24
references: 2408285
references: Br J Pharmacol. 2007 Dec;152(7):1021-32
references: 17618308
references: Nature. 2006 Nov 2;444(7115):106-9
references: 17065983
references: J Physiol. 2011 Apr 15;589(Pt 8):1869-70
references: 21498381
references: Br J Pharmacol. 1999 Apr;126(8):1725-34
references: 10372814
references: J Physiol. 2011 Apr 1;589(Pt 7):1755-67
references: 21282289