The Role of Muscarinic K<sup>+</sup>Channels in the Negative Chronotropic Effect of a Muscarinic Agonist

Yamada, Mitsuhiko

doi:10.1124/jpet.300.2.681

Cited by 52 publications

(49 citation statements)

References 36 publications

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“…Indeed, multiple G␤␥/ GIRK subunit binding events are apparently required to evoke the maximal increase in GIRK channel open probability (Nemec et al, 1999;Sadja et al, 2002Sadja et al, , 2003. Support for this line of reasoning comes from experiments involving the cardiac G-protein-gated potassium channel I KACh (GIRK1/GIRK4 heterotetramer), which represents the dominant but relatively insensitive component of the vagally mediated decrease in heart rate (Yamada, 2002). In atrial myocytes, the cAMP/PKAdependent modulation of the L-type voltage-gated calcium channel and the "pacemaker" current (I f ) occur with ACh concentrations too low to stimulate I KACh (DiFrancesco, 1995).…”

Section: Discussionmentioning

confidence: 99%

Spinal G-Protein-Gated Potassium Channels Contribute in a Dose-Dependent Manner to the Analgesic Effect of μ- and δ- But Not κ-Opioids

Marker¹,

Luján²,

Loh³

et al. 2005

J. Neurosci.

135

130

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Opioids can evoke analgesia by inhibiting neuronal targets in either the brain or spinal cord, and multiple presynaptic and postsynaptic inhibitory mechanisms have been implicated. The relative significance of presynaptic and postsynaptic inhibition to opioid analgesia is essentially unknown, as are the identities and relevant locations of effectors mediating opioid actions. Here, we examined the distribution of G-protein-gated potassium (GIRK) channels in the mouse spinal cord and measured their contribution to the analgesia evoked by spinal administration of opioid receptor-selective agonists. We found that the GIRK channel subunits GIRK1 and GIRK2 were concentrated in the outer layer of the substantia gelatinosa of the dorsal horn. GIRK1 and GIRK2 were found almost exclusively in postsynaptic membranes of putative excitatory synapses, and a significant degree of overlap with the -opioid receptor was observed. Although most GIRK subunit labeling was perisynaptic or extrasynaptic, GIRK2 was found occasionally within the synaptic specialization.

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Section: Discussionmentioning

confidence: 99%

Spinal G-Protein-Gated Potassium Channels Contribute in a Dose-Dependent Manner to the Analgesic Effect of μ- and δ- But Not κ-Opioids

Marker¹,

Luján²,

Loh³

et al. 2005

J. Neurosci.

135

130

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“…IK ACh is present in atrial myocytes where it contributes (together with IK 1 ) to determining the resting membrane potential, the action potential duration and the refractory period. IK ACh is also present in myocytes from the conduction system (SA node, AV node and Purkinje fibre) where it mediates a vagally induced slowing of the heart rate (Yamada, 2002;Yamada et al, 1998). IK ACh is not expressed in ventricular myocytes.…”

Section: Hyperpolarisation-activated Nonselective Cation Current (I Fmentioning

confidence: 99%

Functional effects of the late sodium current inhibition by AZD7009 and lidocaine in rabbit isolated atrial and ventricular tissue and Purkinje fibre

Persson

Andersson

Duker

et al. 2007

European Journal of Pharmacology

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Atrial fibrillation (AF) is the most common tachyarrhythmia in the adult population and is a major cause of morbidity and mortality. AF can be terminated and sinus rhythm restored by prolonging the action potential duration (APD) and the refractory period. Unfortunately, antiarrhythmic agents that prolong the APD and increase the refractory period via selective inhibition of the rapid delayed rectifier potassium current (IK r ), i.e. class III antiarrhythmic drugs, are associated with an increased risk of the ventricular tachycardia Torsades de Pointes. AZD7009 is an antiarrhythmic agent with predominant actions on atrial electrophysiology that shows high antiarrhythmic efficacy and low proarrhythmic potential in animals and man. The aim of the current studies was to characterize the effect of AZD7009 on cardiac ion currents and APD in order to provide a mechanistic explanation for its predominant atrial effects and low proarrhythmic potential.The human cardiac ion channels hERG (IK r ), Kv1.5 (IK ur ), Kv4.3/KChIP2.2 (I to ), KvLQT1/minK (IK s ), Kir3.1/Kir3.4 (IK ACh ) and Nav1.5 (INa) were expressed in mammalian cells. Whole-cell currents were inhibited by AZD7009 with the following IC 50 values: hERG 0.6 μM, Nav1.5 8 μM, Kv4.3/KChIP2.2 24 μM, Kv1.5 27 μM, Kir3.1/Kir3.4 166 μM and KvLQT1/minK 193 μM. Whole-cell sodium and calcium currents were recorded in isolated rabbit atrial and ventricular myocytes using amphotericin B perforated patch. The late sodium current in rabbit atrial and ventricular myocytes was inhibited by AZD7009 in a concentration dependent way, with approximately 50% inhibition at 10 μM AZD7009. The L-type Ca 2+ current (ICa L ) in rabbit ventricular myocytes was inhibited with an IC 50 of 90 μM. Transmembrane action potentials were recorded in tissue pieces from rabbit atrium, ventricle and Purkinje fibre in control, during exposure to the selective IK r blocker E-4031 and to E-4031 in combination with AZD7009. In Purkinje fibres, but not in ventricular tissue, AZD7009 attenuated the E-4031-induced APD prolongation. In contrast, in atrial cells, AZD7009 further prolonged the APD. In addition, AZD7009 was able to suppress early afterdepolarisations (EADs) induced by E-4031 in Purkinje fibre preparations.In conclusion, AZD7009 delays repolarisation and increases refractoriness in atrial tissue through synergistic inhibition of IK r , I to , IK ur and INa, a mixed ion channel blockade that may underlie its high antiarrhythmic efficacy. Inhibition of the late sodium current, counteracting excessive APD prolongation and EADs in susceptible cells (midmyocardial and Purkinje cells), may explain the low proarrhythmic potential of AZD7009.

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“…AChsensitive K ϩ (K ACh ) gives rise to an outward K ϩ current at membrane potentials corresponding to the AP plateau (43). In summary, there are at least three signaling pathways that can, therefore, account for the CCh-induced negative inotropy: 1) activation of the inwardly rectifying current I K ACh and APD shortening (20,54); 2) reduction in AC turnover and cAMP levels (18); and 3) activation of PI3K activity to reduce I CaL (10).…”

Section: Discussionmentioning

confidence: 99%

“…One such compound is tertiapin, a small peptide (21 amino acids) purified from the venom of honey bees (15). Tertiapin selectively blocks I K ACh in cardiac myocytes by acting on the extracellular surface of this K ϩ channel (13,25,54). Tertiapin has little activity on other inward rectifying K ϩ currents, such as I K1 or I KATP , and does not affect either repolarizing K ϩ currents or I CaL (13,25).…”

Section: Discussionmentioning

confidence: 99%

“…Both of these receptor isoforms are coupled to G i . G i -coupled receptors, for example M 2 R, which are responsive to CCh, are known to inhibit cAMP-mediated I CaL , to reduce cell shortening, and to shorten APD (11,18,20,54). An M 2 -G i effect in the sinoatrial node and the atrium also involves activation of an inwardly rectifying K ϩ current: I K ACh .…”

Section: Discussionmentioning

confidence: 99%

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Mechanisms of the negative inotropic effects of sphingosine-1-phosphate on adult mouse ventricular myocytes

Landeen

Dederko²,

Kondo³

et al. 2008

American Journal of Physiology-Heart and Circulatory Physiology

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Landeen LK, Dederko DA, Kondo CS, Hu BS, Aroonsakool N, Haga JH, Giles WR. Mechanisms of the negative inotropic effects of sphingosine-1-phosphate on adult mouse ventricular myocytes. Am J Physiol Heart Circ Physiol 294: H736-H749, 2008. First published November 16, 2007 doi:10.1152/ajpheart.00316.2007.-Sphingosine-1-phosphate (S1P) induces a transient bradycardia in mammalian hearts through activation of an inwardly rectifying K ϩ current (IK ACh ) in the atrium that shortens action potential duration (APD) in the atrium. We have investigated probable mechanisms and receptor-subtype specificity for S1P-induced negative inotropy in isolated adult mouse ventricular myocytes. Activation of S1P receptors by S1P (100 nM) reduced cell shortening by ϳ25% (vs. untreated controls) in fieldstimulated myocytes. S1P 1 was shown to be involved by using the S1P 1-selective agonist SEW2871 on myocytes isolated from S1P3-null mice. However, in these myocytes, S1P 3 can modulate a somewhat similar negative inotropy, as judged by the effects of the S1P 1 antagonist VPC23019. Since S1P1 activates Gi exclusively, whereas S1P 3 activates both Gi and Gq, these results strongly implicate the involvement of mainly G i. Additional experiments using the IK ACh blocker tertiapin demonstrated that IK ACh can contribute to the negative inotropy following S1P activation of S1P 1 (perhaps through Gi␤␥ subunits). Mathematical modeling of the effects of S1P on APD in the mouse ventricle suggests that shortening of APD (e.g., as induced by I K ACh ) can reduce L-type calcium current and thus can decrease the intracellular Ca 2ϩ concentration ([Ca 2ϩ ]i) transient. Both effects can contribute to the observed negative inotropic effects of S1P. In summary, these findings suggest that the negative inotropy observed in S1P-treated adult mouse ventricular myocytes may consist of two distinctive components: 1) one pathway that acts via G i to reduce L-type calcium channel current, blunt calcium-induced calcium release, and decrease [Ca 2ϩ ]i; and 2) a second pathway that acts via Gi to activate IK ACh and reduce APD. This decrease in APD is expected to decrease Ca 2ϩ influx and reduce [Ca 2ϩ ]i and myocyte contractility.calcium; contraction; cell shortening; inhibitory G protein; acetylcholine-sensitive potassium; myocyte SPHINGOSINE-1-PHOSPHATE (S1P) is a biologically active, cell membrane-associated sphingolipid that binds with high affinity to five distinct G-coupled protein receptor isoforms (S1P 1-5 ). S1P 1 has been detected in abundance in neonatal rat cardiomyocytes (39). In these cells, exposure to S1P (500 nM) results in an initial negative inotropic effect (reduction of systolic calcium). However, this may be followed by calcium overload (increased diastolic calcium) and then a cessation of contractility. In isolated atrial myocytes, S1P has been shown to activate a weakly inwardly rectifying potassium (K ϩ ) current. This K ϩ conductance is very similar to the K ϩ current activated by ACh (I K ACh ). Activation of this current can shorte...

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The Role of Muscarinic K⁺Channels in the Negative Chronotropic Effect of a Muscarinic Agonist

Abstract: Acetylcholine causes bradycardia through M2 muscarinic receptors in sinoatrial node cells.

Cited by 52 publications

References 36 publications

Spinal G-Protein-Gated Potassium Channels Contribute in a Dose-Dependent Manner to the Analgesic Effect of μ- and δ- But Not κ-Opioids

Spinal G-Protein-Gated Potassium Channels Contribute in a Dose-Dependent Manner to the Analgesic Effect of μ- and δ- But Not κ-Opioids

Functional effects of the late sodium current inhibition by AZD7009 and lidocaine in rabbit isolated atrial and ventricular tissue and Purkinje fibre

Mechanisms of the negative inotropic effects of sphingosine-1-phosphate on adult mouse ventricular myocytes

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The Role of Muscarinic K+Channels in the Negative Chronotropic Effect of a Muscarinic Agonist

Abstract: Acetylcholine causes bradycardia through M2 muscarinic receptors in sinoatrial node cells.

Cited by 52 publications

References 36 publications

Spinal G-Protein-Gated Potassium Channels Contribute in a Dose-Dependent Manner to the Analgesic Effect of μ- and δ- But Not κ-Opioids

Spinal G-Protein-Gated Potassium Channels Contribute in a Dose-Dependent Manner to the Analgesic Effect of μ- and δ- But Not κ-Opioids

Functional effects of the late sodium current inhibition by AZD7009 and lidocaine in rabbit isolated atrial and ventricular tissue and Purkinje fibre

Mechanisms of the negative inotropic effects of sphingosine-1-phosphate on adult mouse ventricular myocytes

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The Role of Muscarinic K⁺Channels in the Negative Chronotropic Effect of a Muscarinic Agonist