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

• Published in: PloS one 2022-01, Vol.17 (1), p.e0261960
• Main Authors: López-Serrano, Ana Laura, Zamora-Cárdenas, Rodrigo, Aréchiga-Figueroa, Iván A, Salazar-Fajardo, Pedro D, Ferrer, Tania, Alamilla, Javier, Sánchez-Chapula, José A, Navarro-Polanco, Ricardo A, Moreno-Galindo, Eloy G
• Format: Article
• Language: English
• Subjects: Acetylcholine; Adenosine; Heart cells; Medical research; Medicine, Experimental; Membrane potentials; Physiological aspects; Voltage-gated potassium channels
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0261960

Inhibitory regulation of the heart is determined by both cholinergic M.sub.2 receptors (M.sub.2 R) and adenosine A.sub.1 receptors (A.sub.1 R) that activate the same signaling pathway, the ACh-gated inward rectifier K.sup.+ (K.sub.ACh) channels via G.sub.i/o proteins. Previously, we have shown that the agonist-specific voltage sensitivity of M.sub.2 R underlies several voltage-dependent features of I.sub.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.sub.1 R and how this could impact I.sub.KACh . Upon recording whole-cell currents of guinea-pig cardiomyocytes, we found that stimulation of the A.sub.1 R-G.sub.i/o -I.sub.KACh pathway with adenosine only caused a very slight voltage dependence in concentration-response relationships (~1.2-fold EC.sub.50 increase with depolarization) that was not manifested in the relative affinity, as estimated by the current deactivation kinetics ([tau] = 4074 ± 214 ms at -100 mV and [tau] = 4331 ± 341 ms at +30 mV; P = 0.31). Moreover, I.sub.KACh did not exhibit relaxation. Contrarily, activation of the M.sub.2 R-G.sub.i/o -I.sub.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.sub.50 increase with depolarization) and in the I.sub.KACh deactivation kinetics ([tau] = 1762 ± 119 ms at -100 mV and [tau] = 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.sub.KACh relaxation is consequence of this property.