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The agonist-specific voltage dependence of M2 muscarinic receptors modulates the deactivation of the acetylcholine-gated K+ current (I KACh)

  • Ion channels, receptors and transporters
  • Published:
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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.

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Abbreviations

Beth:

Bethanechol

GPCRs:

G protein-coupled receptors

I KACh :

ACh-activated K+ current

Kir:

Inward rectifier K+

M2R:

M2 muscarinic receptor

Pilo:

Pilocarpine

V h :

Membrane holding potential

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Acknowledgments

This work was supported by SEP-CONACYT, México (Grant No. CB-2011-01-167109 (E.G.M.-G) and CB-2013-01-220742 (R.A.N.-P)). The authors wish to thank Miguel Angel Flores-Virgen for the technical assistance.

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Authors and Affiliations

  1. 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

    Eloy G. Moreno-Galindo, José A. Sanchez-Chapula & Ricardo A. Navarro-Polanco

  2. CONACyT Research Fellow, Colima, Mexico

    Javier Alamilla

  3. Nora Eccles Harrison Cardiovascular Research and Training Institute, University of Utah, Salt Lake City, UT, USA

    Martin Tristani-Firouzi

Authors
  1. Eloy G. Moreno-Galindo
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  2. Javier Alamilla
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  3. José A. Sanchez-Chapula
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  4. Martin Tristani-Firouzi
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  5. Ricardo A. Navarro-Polanco
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Corresponding author

Correspondence to Ricardo A. Navarro-Polanco.

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Conflict of interest

The authors declare that they have no conflict of interest, and none of the studies included in our analyses had a conflict of interest.

Ethical approval

All animal studies were performed in accordance with the Guide for the Care and Use of Laboratory Animals published by the US National Institutes of Health (NIH Publication No. 85–23, revised 1996) and after securing approval by the Institutional Animal Care and Use Committee of the University of Colima. This article does not contain any studies with human participants performed by any of the authors.

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Moreno-Galindo, E.G., Alamilla, J., Sanchez-Chapula, J.A. et al. The agonist-specific voltage dependence of M2 muscarinic receptors modulates the deactivation of the acetylcholine-gated K+ current (I KACh). Pflugers Arch - Eur J Physiol 468, 1207–1214 (2016). https://doi.org/10.1007/s00424-016-1812-y

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  • DOI: https://doi.org/10.1007/s00424-016-1812-y

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