Cholinergic and Constitutive Regulation of Atrial Potassium Channel

38


Cholinergic and Constitutive Regulation of Atrial Potassium Channel




Stimulation of the vagal nerve, the principal cardiac arm of the parasympathetic nervous system, reduces heart rate and slows conduction in the atrioventricular node, thereby tuning the heart rate to “rest-and-digest” activities. In 1921, Otto Loewi found that the vagal effects on the heart are mediated by release of acetylcholine (ACh) from the parasympathetic synapses, and ACh became the first neurotransmitter ever discovered.1 However, it took more than 50 years until it was suggested that ACh activates a specific population of K+ channels (ACh-gated IK,ACh; Figure 38-1, A) leading to hyperpolarization of the cell membrane, thereby decreasing pacemaker activity in sinoatrial (SA) node cells.2 It was also found that IK,ACh conductance is voltage dependent, with high K+ conductance at hyperpolarized membrane potentials (at which the current is typically inward) and small conductance at depolarized membrane potentials associated with outward current. This typical current-voltage (IV) relationship designates IK,ACh as an inward-rectifier K+ current (see Figure 38-1, B and C) similar to IK1, which is active in the absence of any receptor agonists, and IK,ATP, which is activated by reduced intracellular ATP levels. Cardiac IK,ACh channels are heterotetramers, usually consisting of two Kir3.1 and two Kir3.4 channel subunits.3



IK,ACh channels are activated by ACh binding to type-2 muscarinic receptors (M2-receptors), which causes dissociation of inhibitory Gi-proteins, thereby increasing IK,ACh open probability via direct interaction of G-protein βγ-subunits with the channel (Figure 38-2, A, B).4,5 After current activation by M2-receptor stimulation, atrial IK,ACh shows a characteristic biphasic desensitization that starts within a few seconds (Figure 38-3, middle). Although both Kir3.1 and Kir3.4 channel homomers produce similar peak-current densities upon M2-receptor stimulation when expressed in HEK-cells, IK,ACh desensitization was observed in Kir3.1 homomers only. Moreover, the desensitization process depends on the presence of the Kir3.1 subunit within the channel complex.6 Besides channel subunit composition, kinetics of G-protein cycle, membrane content of the anionic phospholipid phosphatidylinositol-4,5-bisphosphate (PIP2), and phosphorylation processes also contribute IK,ACh regulation and desensitization (see Figure 38-3).




image


Figure 38-3 Mechanisms contributing to IK,ACh desensitization. Upon muscarinic (M2)-receptor activation, IK,ACh is activated by direct binding of liberated Gβγ-subunits to the IK,ACh channel, followed by a biphasic desensitization (fast and intermediate desensitization). A, The binding of Gβγ-subunits to the IK,ACh channel subunits Kir3.1 and Kir3.4 strengthens their interaction with cell membrane–located phosphatidyl inositol 4,5-bisphosphate (PIP2), thereby increasing IK,ACh open probability. Similarly, increased intracellular Na+ also strengthens the interaction of PIP2 with the channel leading to receptor-independent current activation. In contrast, stimulation of Gq-coupled M1/3-receptors activates phospholipase-C (PLC), thereby lowering the PIP2 membrane content resulting in IK,ACh inhibition and contributing to fast IK,ACh desensitization. B, Regulator of G-protein signaling proteins (RGS) accelerate the GTP hydrolysis rate of the Gαi-subunit, thereby contributing to faster desensitization and reducing agonist-independent constitutive IK,ACh,c activity (see also Figure 38-2, A). C, The phosphorylation of muscarinic (M) receptors and IK,ACh channels is controlled by various kinases and phosphatases, whereby channel phosphorylation increases IK,ACh, while concomitant phosphorylation of M-receptors reduces IK,ACh. Whereas channel dephosphorylation is supposed to contribute to the fast phase (green), the intermediate phase (blue) involves progressive receptor phosphorylation by a G-protein–coupled receptor kinase (GRK), which uncouples the receptor from the G-protein. (Figure was produced using Servier Medical Art.)


Apart from canonical M2-receptor–mediated activation of IK,ACh, purinergic A1,7,8 and sphingolipid Edg-39 receptors (also coupled to Gi-proteins) can activate cardiac IK,ACh channels. Based on their regulation and biophysics, IK,ACh channels are also designated G-protein–activated inwardly rectifying K+ (GIRK) channels. In contrast to ventricular tissue, IK,ACh channels are highly expressed in the atria, including SA and atrioventricular nodes, where they contribute to vagal regulation of heart rate (negative chronotropic effect) and conduction from the atria to the ventricles (negative dromotropic effects).1012




M2-Receptor–Dependent IK,ACh Facilitates Initiation and Maintenance of Atrial Fibrillation


In atrial myocytes, IK,ACh channel activation leads to hyperpolarization of the resting membrane potential and shortening of the action-potential duration (APD).13 ACh-induced APD shortening and resting membrane potential hyperpolarization create an arrhythmogenic substrate facilitating the induction of atrial fibrillation (AF; see also chapter 45 of this book).14 It is well known that vagal nerve stimulation promotes AF in animal models and patients by facilitating the initiation and maintenance of reentry circuits.15 Reentry, the most established basic mechanism of AF, is described as continuous impulse propagation around a functional barrier or an anatomical obstacle. An important requirement for reentry is that the initially activated tissue zone regains excitability while the electrical impulse propagates around the reentry circuit, explaining why reduced effective refractory period or decreased conduction velocity can provide a substrate for AF maintenance. APD shortening induced by IK,ACh activation reduces effective refractory period, thereby favoring AF initiation by vagal stimulation. In knockout mice lacking the Kir3.4 channel subunit, M-receptor stimulation does not induce AF, clearly suggesting that the AF facilitating effects of vagal nerve activation are exclusively mediated by IK,ACh.16 In addition, mathematical modeling studies suggest that increases in an inward-rectifier K+ current such as IK,ACh have a significant role in AF promotion.17 Because of their ability to hyperpolarize atrial cardiomyocytes and remove voltage-dependent Na+-current (INa) inactivation, enhanced inward-rectifier K+ currents are more effective in stabilizing and accelerating AF-sustaining reentry circuits (rotors) than are changes in other ionic currents (e.g., reduced L-type Ca2+ currents) that produce a similar degree of APD shortening. In vivo evidence has been obtained to support the validity of these modeling data.18


Interestingly, AF-related atrial remodeling is associated with reduced maximum activation of IK,ACh upon M-receptor stimulation,13,1922 which might partly result from reduced expression levels of Kir3.1 and Kir3.4 subunits in AF patients.13,21 The reduced agonist-dependent IK,ACh in AF patients could be a protective mechanism against the profibrillatory effects of vagal nerve stimulation.


Left-to-right atrial gradients of inward-rectifier K+ currents contribute to AF pathophysiology. There is clinical and experimental evidence that certain cases of paroxysmal AF (pAF) and chronic AF (cAF) are maintained by high-frequency reentrant sources (rotors) with a consistent left-to-right dominant frequency gradient, particularly in pAF.2325 Because increased inward-rectifier currents enhance rotor frequency, the left-to-right atrial gradient in the basal inward-rectifier current present in pAF, but not in cAF or sinus rhythm (SR), can contribute to these dominant frequency gradients.22 In a sheep model of ACh-mediated, pacing-induced AF, the left-to-right (LA-RA) dominant frequency gradient parallels a left-to-right IK,ACh gradient, supporting the hypothesis that an unequal LA-RA distribution of inward-rectifier K+ currents can contribute to AF maintenance.26 However, in atria from patients with SR, there is a right-to-left atrial gradient of IK,ACh current that is absent in pAF and cAF.22 The lack of RA-dominant agonist-activated IK,ACh could have a permissive role for LA-dominant drivers in pAF and cAF, particularly in vagal contexts.



Agonist-Independent, Constitutively Active IK,ACh Can Contribute to Atrial Fibrillation Maintenance


It is well recognized that IK,ACh can possess agonist-independent “resting” activity, with a much lower opening frequency than agonist-induced IK,ACh.27 Constitutive IK,ACh current (IK,ACh,c) may underlie a major part of basal K+ conductance in SA node cells, which lack IK1, creating an important role in regulating heart rate.28 In the normal heart, constitutive IK,ACh activity is low in atrial myocytes, but can increase substantially with cardiac pathology. Agonist-independent IK,ACh,c activity increases in atrial myocytes from patients and animal models of AF, whereas maximum M-receptor activation of IK,ACh is reduced (see Figure 38-1, C).19,20,22,29 IK,ACh,c might contribute to APD shortening, which is a hallmark of the AF-related electrical remodeling14 (see also Chapter 45). Therefore, agonist-independent IK,ACh,c is expected to increase atrial vulnerability to tachyarrhythmias and to promote persistence of AF. Accordingly, inhibition of IK,ACh with the highly-selective IK,ACh blocker tertiapin reverses the APD abbreviation and prevents the AF promotion in dogs with atrial tachycardia remodeling (ATR) that also develop increased IK,ACh,c.30 IK,ACh is almost absent in ventricles; therefore, it is a promising atrial-selective anti-AF target that lacks proarrhythmic side effects in the ventricles.31


In whole-cell patch-clamp experiments, electrophysiological properties of IK,ACh (i.e., current-voltage relationship) are comparable with other inward-rectifier currents such as IK1 or IK,ATP; therefore, single-channel recordings are often used as a direct index of increased constitutive IK,ACh,c activity in atrial myocytes from patients with cAF and dogs with ATR.19,3234 Due to their short opening-times and a characteristic single-channel conductance of approximately 40 pS IK,ACh single-channel openings are clearly different from openings of IK1 or IK,ATP (Table 38-1). Figure 38-1 shows representative recordings of IK,ACh in the presence and absence of a muscarinic-receptor agonist in atrial myocytes from patients with SR and cAF. Inclusion of the nonselective M-receptor agonist carbachol (10 µM) in the pipette solution strongly activated IK,ACh in both groups, causing frequent channel openings. In the absence of M-receptor agonists, constitutive IK,ACh,c openings are apparent in cAF, whereas they occur only sporadically in myocytes from SR patients.19



In dogs subjected to AF mimicking, atrial tachycardia remodeling IK,ACh also develops agonist-independent constitutive IK,ACh,c activity, suggesting that the development of IK,ACh,c in patients with cAF can result from the high atrial rate rather than from the underlying heart disease.29,30,34 In addition, the alterations in single-channel properties of IK,ACh,c are comparable between dogs with ATR and cAF patients, suggesting a common molecular basis.34 The complex regulation of IK,ACh points to several possible mechanisms that could contribute to the development of IK,ACh,c. The following discussion summarizes the current knowledge about the molecular regulation of agonist-dependent IK,ACh in atrial myocytes, particularly focusing on the putative mechanisms underlying constitutive IK,ACh activity in AF.



G-Protein Cycle Can Contribute to the Generation of Constitutive IK,ACh



M2-Receptor–Dependent IK,ACh


Inward-rectifier IK,ACh channels are activated through stimulation of appropriate Gi-protein–coupled receptors (M2-receptors), resulting in the dissociation of heterotrimeric Gi-proteins and consecutive binding of Gβγ-subunits to the channel (see Figure 38-2, A, B).38 Heterotrimeric G-proteins are composed of two functional units, the guanosine-5′-diphosphate and guanosine-5′-triphosphate (GDP/GTP) binding Gα-subunit and the Gβγ-dimer. Upon stimulation of G-protein–coupled receptors, GDP (bound to the Gα-subunit under resting conditions) is released and replaced by GTP. The resulting conformational changes lead to a dissociation of Gα and Gβγ subunits, which then initiate and regulate multiple intracellular pathways. Intrinsic GTPase activity of the Gα-subunit results in GTP hydrolysis into GDP followed by reassembly of the G-protein subunits and reestablishment of the initial inactive state.39 Gα-subunits are subdivided into Gαs-subunits, which stimulate adenylate cyclases, Gαi-subunits, which inhibit adenylate cyclases, and Gαq-subunits, which activate phospholipase-C (see later). IK,ACh

Only gold members can continue reading. Log In or Register to continue

Stay updated, free articles. Join our Telegram channel

Jun 5, 2016 | Posted by in CARDIAC SURGERY | Comments Off on Cholinergic and Constitutive Regulation of Atrial Potassium Channel

Full access? Get Clinical Tree

Get Clinical Tree app for offline access