Short-Term Desensitization of Muscarinic K+ Current in the Heart

Abstract

Acetylcholine (ACh) rapidly increases cardiac K(+) currents (IKACh) by activating muscarinic K(+) (KACh) channels followed by a gradual amplitude decrease within seconds. This phenomenon is called short-term desensitization and its precise mechanism and physiological role are still unclear. We constructed a mathematical model for IKACh to examine the conditions required to reconstitute short-term desensitization. Two conditions were crucial: two distinct muscarinic receptors (m2Rs) with different affinities for ACh, which conferred an IKACh response over a wide range of ACh concentrations, and two distinct KACh channels with different affinities for the G-protein βγ subunits, which contributed to reconstitution of the temporal behavior of IKACh. Under these conditions, the model quantitatively reproduced several unique properties of short-term desensitization observed in myocytes: 1), the peak and quasi-steady states with 0.01-100 μM [ACh]; 2), effects of ACh preperfusion; and 3), recovery from short-term desensitization. In the presence of 10 μM ACh, the IKACh model conferred recurring spontaneous firing after asystole of 8.9 s and 10.7 s for the Demir and Kurata sinoatrial node models, respectively. Therefore, two different populations of KACh channels and m2Rs may participate in short-term desensitization of IKACh in native myocytes, and may be responsible for vagal escape at nodal cells.

The Roles of Gβγ and Gα in Gating and Regulation of GIRK Channels

“…The cooperative nature of GIRK gating is in good agreement with considerations based on structural studies: several molecules of Gβγ may be needed to produce sufficient mechanical strain to cause relative rotation of GIRK's cytoplasmic domains, which is then translated into gate opening (Whorton & MacKinnon, 2013). Based on the assumption of cooperative action of four Gβγ molecules, Kurachi and collaborators (Hosoya, Yamada, Ito, & Kurachi, 1996;Murakami, Inanobe, & Kurachi, 2013;Murakami, Suzuki, Ishii, Inanobe, & Kurachi, 2010) have developed an allosteric Monod-Wyman-Changeux-type model which adequately describes the magnitude and kinetics (but not I basal ), and the effect of RGS proteins, for the cardiac I KACh .…”

A Collision Coupling Model Governs the Activation of Neuronal GIRK1/2 Channels by Muscarinic-2 Receptors

“…Though all these models implement Thomsen-Neubig style G-protein activation model ( Thomsen and Neubig, 1989 ; Zhong et al, 2003 ), they differ in certain key details. In particular, the model proposed by Murakami et al (2013) assumes two affinity states of GIRK to Gβγ and two affinity states of GPCR to agonist; however, the GPCR-agonist affinity states are not kinetically interconnected and unrelated to coupling to G-protein. These are incompatible with the well-established dependency of agonist affinity upon the G protein-GPCR association ( Maguire et al, 1976 ; De Lean et al, 1980 ; Haga et al, 1986 ; Weis and Kobilka, 2018 ).…”

“…The process that leads to GIRK opening following the binding of Gβγ is still unclear ( Glaaser and Slesinger, 2017 ). Currently there are three detailed GIRK gating models developed chronologically by Kurachi group ( Hosoya et al, 1996 ; Murakami et al, 2010 ; Murakami et al, 2013 ), our group ( Yakubovich et al, 2005 ; Yakubovich et al, 2015 ) and MacKinnon’s group ( Touhara et al, 2016 ; Wang et al, 2016 ; Touhara and MacKinnon, 2018 ). The model proposed by Kurachi’s group is based on Monod-Wyman-Changeux allosteric model of GIRK activation and formulates two binding states of Gβγ for each channel subunit.…”

“…The first model of GIRK activation that also incorporated a G protein cycle of GIRK activation was published in 1988 (Breitwieser and Szabo, 1988). Subsequently, updated models have been developed by groups of Kurachi and Mackinnon (Murakami et al, 2010;Murakami et al, 2013;Touhara and MacKinnon, 2018). Though all these models implement Thomsen-Neubig style G-protein activation model (Thomsen and Neubig, 1989;Zhong et al, 2003), they differ in certain key details.…”

Cardiac Resynchronization Therapy Restores Sympathovagal Balance in the Failing Heart by Differential Remodeling of Cholinergic Signaling

“…Extensive in vitro and ex vivo evidence indicates Gαi-coupled cardiac M2-mAChRs are activated in proportion to Gαi expression 25 and in this setting, atropine may act as an inverse agonist 16 . These chronically-activated M2-mAChRs may be susceptible to agonist-induced desensitization 26, 27 , a well-characterized phenomenon that may be a mechanism for the improved hemodynamics 14 noted with tonic cholinergic stimulation in ongoing clinical HF trials 12, 13, 28 .…”