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

Moreno‐Galindo, Eloy G.; Alamilla, Javier; Sánchez-Chapula, José A.; Tristani‐Firouzi, Martin; Navarro‐Polanco, Ricardo A.

doi:10.1007/s00424-016-1812-y

Cited by 26 publications

(21 citation statements)

References 21 publications

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“…Charge movements within membrane proteins, such as the coupled transfer of Na + ions and protons suggested by our MD simulations and p K a calculations, should be sensitive to the membrane voltage. Indeed, it has been demonstrated that GPCR signaling is modulated by membrane voltage changes (Vickery, Machtens, Tamburrino, et al 2016; Martinez-Pinna et al 2004; Rinne et al 2015; Mahaut-Smith et al 2008; Ben-Chaim et al 2006; Moreno-Galindo et al 2016). This applies both to the conformation of the receptors as well as their transmitted signal.…”

Section: Discussionmentioning

confidence: 99%

Intracellular Transfer of Na+ in an Active-State G-Protein-Coupled Receptor

et al. 2018

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Playing a central role in cell signaling, G-protein-coupled receptors (GPCRs) are the largest superfamily of membrane proteins and form the majority of drug targets in humans. How extracellular agonist binding triggers the activation of GPCRs and associated intracellular effector proteins remains, however, poorly understood. Structural studies have revealed that inactive class A GPCRs harbor a conserved binding site for Na ions in the center of their transmembrane domain, accessible from the extracellular space. Here, we show that the opening of a conserved hydrated channel in the activated state receptors allows the Na ion to egress from its binding site into the cytosol. Coupled with protonation changes, this ion movement occurs without significant energy barriers, and can be driven by physiological transmembrane ion and voltage gradients. We propose that Na ion exchange with the cytosol is a key step in GPCR activation. Further, we hypothesize that this transition locks receptors in long-lived active-state conformations.

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Section: Discussionmentioning

confidence: 99%

Intracellular Transfer of Na+ in an Active-State G-Protein-Coupled Receptor

et al. 2018

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“…Since this first discovery at the M2-receptor, a number of GPCRs have been investigated under this aspect (reviewed in: Vickery et al, 2016). The majority of investigated GPCRs showed voltage dependence and the effect that voltage had on GPCR activity was ligand-specific (Navarro-Polanco et al, 2011;Sahlholm et al, 2011;Rinne et al, 2013Rinne et al, , 2015Birk et al, 2015;Moreno-Galindo et al, 2016). Voltage was able to alter either affinity, efficacy, or both (Rinne et al, 2013;Birk et al, 2015).…”

Section: Introductionmentioning

confidence: 99%

Voltage Dependence of Prostanoid Receptors

2020

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G protein-coupled receptors (GPCRs) are the largest class of transmembrane receptors and serve as signal mediators to transduce information from extracellular signals such as neurotransmitters, hormones, or drugs to cellular responses. They are exposed to the strong electrical field of the plasma membrane. In the last decade voltage modulation of ligand-induced GPCR activity has been reported for several GPCRs. Using Foerster resonance energy transfer-based biosensors in patch clamp experiments, we discovered a robust voltage dependence of the thromboxane receptor (TP receptor) on the receptor level as well as on downstream signaling. TP receptor activity doubled upon depolarization from 290 to 160 mV in the presence of U46619, a stable analog of prostaglandin H 2. Half-maximal effective potential (V 0.5) determined for TP receptor was 246 mV, which is within the physiologic range. We identified that depolarization affected the agonist affinity for the TP receptor. Depolarization enhanced responses of several structural analogs of U46619 with modifications to a similar extent all around the molecule, indicating that voltage modulates the general conformation of TP receptor. By means of site direct mutagenesis, we identified TP receptor R295 7.40 , which showed alteration of voltage sensitivity of TP receptor upon mutation. Voltage sensitivity was not limited to TP receptor because prostaglandin F receptor activated with U46619 and prostaglandin E 2 receptor subtype 3 activated with iloprost showed a similar reaction to depolarization as TP receptor. However, prostacyclin receptor activated with iloprost showed no detectable voltage dependence. SIGNIFICANCE STATEMENT Prostanoids mediate many of their physiological effects via transmembrane receptors expressed in the plasma membrane of excitable cells. We found that agonist-mediated activation of prostaglandin F receptors and prostaglandin E 2 receptors as well as thromboxane receptors are activated upon depolarization, whereas prostacyclin receptors are not. The voltage-induced modulation of thromboxane receptor activity was observed on the level of receptor conformation and downstream signaling. The range of voltage dependence was restricted by R295 7.40 in the agonist-binding pocket.

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“…Charge movements within membrane proteins, such as the coupled transfer of Na + ions and protons suggested by our MD simulations and pK a calculations, should be sensitive to the membrane voltage. Indeed, it has been demonstrated that GPCR signalling is modulated by membrane voltage changes 22,23,39,[47][48][49] . This applies both to the conformation of the receptors as well as their transmitted signal.…”

Section: Discussionmentioning

confidence: 99%