title: The agonist-specific voltage dependence of M2 muscarinic receptors modulates the deactivation of the acetylcholine-gated K(+) current (I KACh).
abstract: Recently, it has been shown that G protein-coupled receptors (GPCRs) display intrinsic voltage sensitivity. We reported that the voltage sensitivity of M2 muscarinic receptor (M2R) is also ligand specific. Here, we provide additional evidence to understand the mechanism underlying the ligand-specific voltage sensitivity of the M2R. Using ACh, pilocarpine (Pilo), and bethanechol (Beth), we evaluated the agonist-specific effects of voltage by measuring the ACh-activated K(+) current (I KACh) in feline and rabbit atrial myocytes and in HEK-293 cells expressing M2R-Kir3.1/Kir3.4. The activation of I KACh by the muscarinic agonist Beth was voltage insensitive, suggesting that the voltage-induced conformational changes in M2R do not modify its affinity for this agonist. Moreover, deactivation of the Beth-evoked I KACh was voltage insensitive. By contrast, deactivation of the ACh-induced I KACh was significantly slower at -100 mV than at +50 mV, while an opposite effect was observed when I KACh was activated by Pilo. These findings are consistent with the voltage affinity pattern observed for these three agonists. Our findings suggest that independent of how voltage disturbs the receptor binding site, the voltage dependence of the signaling pathway is ultimately determined by the agonist. These observations emphasize the pharmacological potential to regulate the M2R-parasympathetic associated cardiac function and also other cellular signaling pathways by exploiting the voltage-dependent properties of GPCRs.
authors.affiliation: Centro Universitario de Investigaciones Biomedicas, C.U.I.B, Universidad de Colima, Av. 25 de Julio 965, Colonia Villa San Sebastián, 28045, Colima, COL, Mexico.
authors.forename: Eloy G
authors.initials: EG
authors.lastname: Moreno-Galindo
authors.affiliation: CONACyT Research Fellow, Colima, Mexico.
authors.forename: Javier
authors.initials: J
authors.lastname: Alamilla
authors.affiliation: Centro Universitario de Investigaciones Biomedicas, C.U.I.B, Universidad de Colima, Av. 25 de Julio 965, Colonia Villa San Sebastián, 28045, Colima, COL, Mexico.
authors.forename: José A
authors.initials: JA
authors.lastname: Sanchez-Chapula
authors.affiliation: Nora Eccles Harrison Cardiovascular Research and Training Institute, University of Utah, Salt Lake City, UT, USA.
authors.forename: Martin
authors.initials: M
authors.lastname: Tristani-Firouzi
authors.affiliation: Centro Universitario de Investigaciones Biomedicas, C.U.I.B, Universidad de Colima, Av. 25 de Julio 965, Colonia Villa San Sebastián, 28045, Colima, COL, Mexico. magdal@ucol.mx.
authors.forename: Ricardo A
authors.initials: RA
authors.lastname: Navarro-Polanco
mesh_terms: D000109:Acetylcholine / Q000494:pharmacology*; D000818:Animals; D001665:Binding Sites / Q000187:drug effects; D002415:Cats; D051676:G Protein-Coupled Inwardly-Rectifying Potassium Channels / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D015640:Ion Channel Gating / Q000187:drug effects*; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects; D018721:Muscarinic Agonists / Q000494:pharmacology*; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism; D011188:Potassium / Q000378:metabolism*; D015221:Potassium Channels / Q000378:metabolism*; D011817:Rabbits; D043585:Receptor, Muscarinic M2 / Q000378:metabolism*; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D051676:G Protein-Coupled Inwardly-Rectifying Potassium Channels; D018721:Muscarinic Agonists; D015221:Potassium Channels; D043585:Receptor, Muscarinic M2; D043562:Receptors, G-Protein-Coupled; D000109:Acetylcholine; D011188:Potassium
keywords: Cardiac myocytes; G protein-coupled receptors; I KACh; Muscarinic receptors