For example, numerous disease-causing mutations in ion channel genes alter the voltage sensitivity of the channel [ 18 , 19 ]. In light of these observations, we simulated effects of hypothetical mutation-induced positive and negative shifts in M2R voltage sensitivity to ACh on sinus node AP properties and spontaneous firing. These simulations provide a proof-of-principle for a theoretical contribution of altered M2R voltage sensitivity to cardiovascular disease states associated with changes in vagal tone.
For example, parasympathetic induction and maintenance of atrial arrhythmias is a well-described phenomenon, first reported in [ 20 ]. Moreover, increased parasympathetic tone is an initiating factor in a subset of AF patients [ 21 ]. These genetic variants might explain, in part, the clinical phenotype of vagally-mediated AF patients who present with bradycardia in the setting of physiological basal ACh concentrations.
Thus, positive shifts in M2R voltage sensitivity would decrease the effects of vagal modulation of heart rate, thereby increasing basal heart rate, as observed in the syndrome of IST. Indeed, a recent study confirmed decreased parasympathetic tone in IST patients [ 22 ]. While speculative, the hypothesis that altered M2R voltage sensitivity is relevant for cardiac diseases provides a novel mechanistic foundation to study disorders such as AF and IST.
There are several limitations inherent in the application of the model to describe the kinetics and behavior of I K , ACh. First, the receptor-channel model was fit and optimized to recreate the kinetics of I K , ACh occurring at a concentration of 0. While this is within the range of measured concentrations of ACh, measurements at lower concentrations could enable a more accurate reconstruction of the behavior of I K , ACh and a direct comparison to the effect of I f at such concentrations.
This simplification was necessary as parameters for more complex models are not identifiable with the existent experimental data. Also, the model is not able to reproduce the distinct characteristics of the deactivation protocol time constants. The experimental data indicate that the deactivation time constant is nearly voltage-independent Fig 3H , the model predicts an increase with membrane depolarization. Nonetheless, because the other simulated features have a very high similarity to the measured values Fig 3B, 3C, 3F and 3G and the time constants are in the range of less than half the length of an action potential, we believe that any error introduced does not significantly influence our findings.
The SN cell model recapitulates the experimental findings that ACh inhibits I f and I Ca , L , which also contribute to slowing of spontaneous pacing rate [ 23 ]. The recent observation that M2Rs are intrinsically voltage sensitive has important implications for understanding the physiology and pathophysiology of parasympathetic regulation of heart rate and APD. By optimizing and integrating a new Markovian model into a human SN model, we show that low ACh concentrations preferentially slow beating rate, without shortening APD, and thereby provide additional support that I K , ACh participates in the purely chronotropic effects of basal vagal tone.
Moreover, we explore the effects of altered M2R voltage sensitivity and provide a proof-of-principle foundation that altered sensitivity could result in clinical manifestations of disease states such as vagally-mediated atrial fibrillation and syndrome of inappropriate sinus tachycardia.
Given the importance of parasympathetic regulation of atrial vulnerability, M2Rs represent an important therapeutic target to control or prevent atrial arrhythmias.
We developed a Markovian model to reconstruct the behavior of K ACh channels at different ACh concentrations and varying transmembrane voltages Fig 2. This sub-model describes biophysical properties of the M2R and comprises 4 distinct states, U1 , B1 , U2 and B2 , whose interaction describes the affinity of M2R to changes in ACh concentration [L] and transmembrane voltage V m Fig 2 , left side. The sub-model was published previously [ 5 ] and is a simplification of a more complex model of receptor systems [ 24 ].
Each of the 4 distinct states represents the M2R under specific conditions. The transition rate coefficients between these states are dependent on V m or [L]. Additionally to the original formulation, we introduced a voltage shift V shift to describe effects of mutations on voltage sensitivity of the receptor.
The shift solely affects the voltage dependent transition rate coefficients of the M2R and thus indirectly influences the states of the K ACh channel model and the resulting I K , ACh. We defined negative V shift as hyperpolarizing shifts. Negative V shift lead to an increased occupancy of the states U1 and B1, i.
Likewise, positive V shift were defined as depolarizing shifts as they lead to increased occupancy of the states U2 and B2, i. A change in voltage affinity due to the presence of ACh was represented as a change in the transition rate. A previously developed description for I K , ACh was used to calculate this current [ 23 ].
The parameters of the model were determined by iterative stochastic optimization as previously described [ 5 ]. An error function based on the root mean squared differences of the measured versus simulated features of the activation protocol, deactivation protocol, and concentration response curve from [ 5 ] was minimized.
Measured features were based on whole-cell voltage-clamp experiments [ 5 ]. I K , ACh for the activation and deactivation clamp protocols was recorded in the presence of 0.
We choose this strategy, as extracting mono-exponential features and then averaging them introduces less error in the overall reconstructed behavior than averaging the signals themselves. The same fitting approach was used during the model parameterization.
The currents were then normalized to the current measured at maximal ACh concentration for each holding potential. A total of 8 simulated features f s,i , consisting of six features for the voltage clamp protocols i. Other components of the cost function were used to constrain the behavior of the model at specific ACh concentration and V m , and to ensure high open probability of the channel.
Respectively, U1 was forced to be maximal without bound ACh and a transmembrane voltage of mV. Further, the sum of B1 and B2 was forced to be maximal with bound ACh. For simulations of single cell electrophysiology, the new receptor-channel model was integrated in the publically available model of human SN cells [ 6 ]. Numerical integration was performed by using the integrated ode15s formulation provided by Matlab.
The maximum conductivity g K , ACh , max was set 0. The stochastic parameterization yielded the model parameters Table 3. In comparison to the parameterization of our previous model [ 5 ], the fit error of the features from the activation and deactivation protocols was reduced from 1. The total error of the features is equal to the square root of the sum of the respective squared fit errors. The corresponding modeled and measured current traces of the voltage protocols are shown in S2 Fig.
The concentration-response curves are voltage-dependent, whereby negative holding potentials are associated with greater ACh binding affinity, while depolarized holding potentials decrease binding affinity. Ditz D. Zolk O. Eschenhagen T. Decreased protein and phosphorylation level of the protein phosphatase inhibitor-1 in failing human hearts Cardiovasc.
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Sign In or Create an Account. Sign In. Advanced Search. Search Menu. Article Navigation. Close mobile search navigation Article Navigation. Volume Article Contents Abstract. Physiological roles of cTnI phosphorylation. Alterations in cTnI phosphorylation in pathological states. Regulation of cardiac contractile function by troponin I phosphorylation.
Joanne Layland , Joanne Layland. Oxford Academic. John Solaro. Ajay M. Email address: ajay. Time for primary review 25 days. Revision received:. Cite Cite Joanne Layland, R. Select Format Select format. Permissions Icon Permissions. Myocardial contractility , Troponin I , Phosphorylation , Protein kinases.
Open in new tab Download slide. Proteins that switch on and tune in the activity of cardiac myofilaments. Google Scholar Crossref. Search ADS. Myofilament properties comprise the rate-limiting step for cardiac relaxation at body temperature in the rat. Thin filament-based modulation of contractile performance in human heart failure. The essential role of troponin in cardiac muscle regulation. Adrenaline increases the rate of cycling of crossbridges in rat cardiac muscle as measured by pseudo-random binary noise-modulated perturbation analysis.
Adrenaline increases the rate of cross-bridge cycling in rat cardiac muscle. Cardiac troponin-I phosphorylation increases the rate of cardiac muscle relaxation. Impaired cardiomyocyte relaxation and diastolic function in transgenic mice expressing slow skeletal troponin I in the heart. Phosphorylation of troponin-I by protein kinase A accelerates relaxation and crossbridge cycle kinetics in mouse ventricular muscle. Power output is increased after phosphorylation of myofibrillar proteins in rat skinned cardiac myocytes.
Lack of effect of isoproterenol on unloaded velocity of sarcomere shortening in rat cardiac trabeculae. Effects of phosphorylation of Troponin I and C-protein on isometric tension and velocity of unloaded shortening in skinned single cardiac myocytes from rats. Protein kinase A does not alter unloaded velocity of sarcomere shortening in skinned rat cardiac trabeculae.
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Peroxynitrite-induced cardiac depression: role of myofilament desensitization and cGMP pathway. Effects of damaging the endocardial surface on the mechanical performance of isolated cardiac muscle.
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Ryan Strachan, Dr. Laura Wingler, Dr. Neil Freedman, Dr. Richard Premont, and Dr. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. HL , C. G HD , J. HL , P. DK , W. RCA , M. HL and HL All data generated or analyzed during this study are included in this published article and its supplementary information files.
Jihee Kim, James W. Rosenberg, Howard A.
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