Voltage-induced structural modifications on M2 muscarinic receptor and their functional implications when interacting with the superagonist iperoxo

López-Serrano, Ana Laura; Jesús-Pérez, José J. De; Zamora-Cárdenas, Rodrigo; Ferrer, Tania; Rodríguez-Menchaca, Aldo A.; Tristani‐Firouzi, Martin; Moreno‐Galindo, Eloy G.; Navarro‐Polanco, Ricardo A.

doi:10.1016/j.bcp.2020.113961

Cited by 7 publications

(10 citation statements)

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“…This property is strikingly reduced by high ACh concentrations (Fig 6B and 6C) due to the maximal activation of K ACh channels both at negative and positive potentials. These results are consistent with those obtained in feline cardiomyocytes with the superagonist iperoxo [34]. In the activation of the A 1 R-G i/o -I KACh pathway with Ado, the slight voltage dependence detected in the C-R curves (Fig 1 ) was not reflected in the relative affinity assessed by the current deactivation kinetics (Fig 2) [29,30]; and thus time-dependent changes of the current upon modifying the membrane voltage (relaxation) were not observed (Fig 3).…”

Section: Plos Onesupporting

confidence: 92%

“…Alternatively, our data are more compatible with the idea that membrane potential induces conformational changes directly at the agonist binding (orthosteric) site of GPCRs, independent of G-protein coupling, which determine the modulation of the remainder signaling pathway [9,11,15,20,22]. Thus, regardless of the same effector of both cardiac signaling pathways, in M 2 R the hyperpolarizationinduced conformational changes (at the orthosteric site and the external access [34,37]) provoke an increase in the affinity for ACh [8,11,28] that yields a higher stimulation of downstream cellular elements. In A 1 R, it is conceivable that voltage also alters its molecular conformation but in such a manner that only a very slight change in the potency (probably the affinity) for Ado is generated (Fig 1), which is not mirrored in other less sensitive functional assays (deactivation kinetics and currents evoked with voltage step protocols).…”

Section: Plos Onesupporting

confidence: 82%

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Differential voltage-dependent modulation of the ACh-gated K+ current by adenosine and acetylcholine

et al. 2022

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Inhibitory regulation of the heart is determined by both cholinergic M2 receptors (M2R) and adenosine A1 receptors (A1R) that activate the same signaling pathway, the ACh-gated inward rectifier K+ (KACh) channels via Gi/o proteins. Previously, we have shown that the agonist-specific voltage sensitivity of M2R underlies several voltage-dependent features of IKACh, including the ‘relaxation’ property, which is characterized by a gradual increase or decrease of the current when cardiomyocytes are stepped to hyperpolarized or depolarized voltages, respectively. However, it is unknown whether membrane potential also affects A1R and how this could impact IKACh. Upon recording whole-cell currents of guinea-pig cardiomyocytes, we found that stimulation of the A1R-Gi/o-IKACh pathway with adenosine only caused a very slight voltage dependence in concentration-response relationships (~1.2-fold EC50 increase with depolarization) that was not manifested in the relative affinity, as estimated by the current deactivation kinetics (τ = 4074 ± 214 ms at -100 mV and τ = 4331 ± 341 ms at +30 mV; P = 0.31). Moreover, IKACh did not exhibit relaxation. Contrarily, activation of the M2R-Gi/o-IKACh pathway with acetylcholine induced the typical relaxation of the current, which correlated with the clear voltage-dependent effect observed in the concentration-response curves (~2.8-fold EC50 increase with depolarization) and in the IKACh deactivation kinetics (τ = 1762 ± 119 ms at -100 mV and τ = 1503 ± 160 ms at +30 mV; P = 0.01). Our findings further substantiate the hypothesis of the agonist-specific voltage dependence of GPCRs and that the IKACh relaxation is consequence of this property.

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Section: Plos Onesupporting

confidence: 92%

Section: Plos Onesupporting

confidence: 82%

Differential voltage-dependent modulation of the ACh-gated K+ current by adenosine and acetylcholine

et al. 2022

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“…The depolarization-induced decrease in acetylcholine potency at the M 2 R has been related to a corresponding increase in acetylcholine k off at the M 2 R, and a consequent increase in GIRK response deactivation rate at depolarized potentials (Ben-Chaim et al, 2003;Ben Chaim et al, 2013;Agren et al, 2018b;Loṕez-Serrano et al, 2020). Similar findings have been reported for the mGluR3 and histamine H 3 receptors (Ohana et al, 2006;Sahlholm et al, 2012).…”

Section: Discussionsupporting

confidence: 76%

Voltage-Dependent Dopamine Potency at D1-Like Dopamine Receptors

Ågren

Sahlholm

2020

Front. Pharmacol.

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In recent years, transmembrane voltage has been found to modify agonist potencies at several G protein-coupled receptors (GPCRs). Whereas the voltage sensitivities of the Ga i/o-coupled dopamine D 2-like receptors (D 2 R, D 3 R, D 4 R) have previously been investigated, the putative impact of transmembrane voltage on agonist potency at the mainly Ga s/olf-coupled dopamine D 1-like receptors (D 1 R, D 5 R) has hitherto not been reported. Here, we assayed the potency of dopamine in activating G protein-coupled inward rectifier potassium (GIRK) channels co-expressed with D 1 R and D 5 R in Xenopus oocytes, at-80 mV and at 0 mV. Furthermore, GIRK response deactivation rates upon dopamine washout were measured to estimate dopamine dissociation rate (k off) constants. Depolarization from-80 to 0 mV was found to reduce dopamine potency by about 7-fold at both D 1 R and D 5 R. This potency reduction was accompanied by an increase in estimated dopamine k off s at both receptors. While the GIRK response elicited via D 1 R was insensitive to pertussis toxin (PTX), the response evoked via D 5 R was reduced by 64% (-80 mV) and 71% (0 mV) in the presence of PTX. Injection of oocytes with Ga s antisense oligonucleotide inhibited the D 1 R-mediated response by 62% (-80 mV) and 76% (0 mV) and abolished the D 5 R response when combined with PTX. Our results suggest that depolarization decreases dopamine affinity at D 1 R and D 5 R. The voltagedependent affinities of dopamine at D 1 R and D 5 R may be relevant to the functions of these receptors in learning and memory.

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“…A strong influence on ligand-specific voltage sensitivity of helices 3 and 6 was also reported for the muscarinic M3 receptor (Rinne et al, 2015). In general, there is still a lot of speculation about a possible general voltage sensing mechanism for GPCRs (Barchad-Avitzur et al, 2016;Hoppe et al, 2018;López-Serrano et al, 2020;Vickery et al, 2016). In this context, the involvement of a sodium ion bound to a conserved D was discussed (Vickery et al, 2016).…”

Section: Discussionmentioning

confidence: 86%

Differential recognition of opioid analgesics by µ opioid receptors: Predicted interaction patterns correlate with ligand-specific voltage sensitivity

Kirchhofer

Lim

Julia

et al. 2021

Preprint

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The µ opioid receptor (MOR) is the key target for analgesia, but the application of opioids is accompanied by several issues. There is a wide range of opioid analgesics, differing in their chemical structure and their properties in receptor activation and subsequent effects. A better understanding of ligand-receptor interactions and resulting effects is important. Here, we calculated the respective binding modes for several opioids and analyzed fingerprints of ligand-receptor interactions. We further corroborated the binding modes experimentally by cellular assays. As ligand-induced modulation of activity due to changes in membrane potential was displayed by MOR, we further analyzed the effects of voltage sensitivity of this receptor. With a combined in silico and in vitro approach, we defined discriminating interaction patterns for the ligand-specific voltage sensitivity. With this, we present new insights for interactions likely in ligand recognition and their specific effects on activation of the MOR.

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Voltage-induced structural modifications on M2 muscarinic receptor and their functional implications when interacting with the superagonist iperoxo

Cited by 7 publications

References 40 publications

Differential voltage-dependent modulation of the ACh-gated K+ current by adenosine and acetylcholine

Differential voltage-dependent modulation of the ACh-gated K+ current by adenosine and acetylcholine

Voltage-Dependent Dopamine Potency at D1-Like Dopamine Receptors

Differential recognition of opioid analgesics by µ opioid receptors: Predicted interaction patterns correlate with ligand-specific voltage sensitivity

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