In:
PLOS ONE, Public Library of Science (PLoS), Vol. 17, No. 1 ( 2022-1-14), p. e0261960-
Abstract:
Inhibitory regulation of the heart is determined by both cholinergic M 2 receptors (M 2 R) and adenosine A 1 receptors (A 1 R) that activate the same signaling pathway, the ACh-gated inward rectifier K + (K ACh ) channels via G i/o proteins. Previously, we have shown that the agonist-specific voltage sensitivity of M 2 R underlies several voltage-dependent features of I KACh , 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 A 1 R and how this could impact I KACh . Upon recording whole-cell currents of guinea-pig cardiomyocytes, we found that stimulation of the A 1 R-G i/o - I KACh pathway with adenosine only caused a very slight voltage dependence in concentration-response relationships (~1.2-fold EC 50 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, I KACh did not exhibit relaxation. Contrarily, activation of the M 2 R-G i/o - I KACh 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 EC 50 increase with depolarization) and in the I KACh 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 I KACh relaxation is consequence of this property.
Type of Medium:
Online Resource
ISSN:
1932-6203
DOI:
10.1371/journal.pone.0261960
DOI:
10.1371/journal.pone.0261960.g001
DOI:
10.1371/journal.pone.0261960.g002
DOI:
10.1371/journal.pone.0261960.g003
DOI:
10.1371/journal.pone.0261960.g004
DOI:
10.1371/journal.pone.0261960.g005
DOI:
10.1371/journal.pone.0261960.g006
DOI:
10.1371/journal.pone.0261960.s001
DOI:
10.1371/journal.pone.0261960.s002
DOI:
10.1371/journal.pone.0261960.s003
DOI:
10.1371/journal.pone.0261960.s004
DOI:
10.1371/journal.pone.0261960.r001
DOI:
10.1371/journal.pone.0261960.r002
DOI:
10.1371/journal.pone.0261960.r003
DOI:
10.1371/journal.pone.0261960.r004
DOI:
10.1371/journal.pone.0261960.r005
DOI:
10.1371/journal.pone.0261960.r006
Language:
English
Publisher:
Public Library of Science (PLoS)
Publication Date:
2022
detail.hit.zdb_id:
2267670-3
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