Mutation in one Molecule Induces Beating Rate Changes by Affecting the Coupled Clock Pacemaker Function
Yael Yaniv* and Joachim A Behar
Biomedical Engineering Faculty, Technion-IIT, Israel
Submission: July 07, 2017; Published: July 26, 2017
*Corresponding author: Yael Yaniv, Laboratory of Bioenergetic and Bioelectric Systems, Biomedical Engineering Faculty, Technion-IIT, Haifa, Israel, Tel: 972-4-8294124 ; Fax: 972-4-8294599; Email: firstname.lastname@example.org
How to cite this article: Yael Y, Joachim A B. Mutation in one Molecule Induces Beating Rate Changes by Affecting the Coupled Clock Pacemaker Function . J Cardiol & Cardiovasc Ther 2017; 6(4): 555695. DOI: 10.19080/JOCCT.2017.06.555695.
Pacemaker function is orchestrated through molecules on the membrane and on the sarcoplasmic reticulum that are coupled by Ca2+ and post-translation modification signaling. These molecules and signaling cascades form one coupled-clock system. Experimental and computational evidence highlight the coupling between components in this system. However, most studies examine how a given pacemaker mutation causes bradycardia or tachycardia and report changes only for the affected molecule without capturing the overall effect on the coupled-clock system. Here, we provide our opinion on how a mutation in one molecule impacts the beating rate by affecting the coupled clock pacemaker function (and thus not only a single molecule). A better understanding of changes in the coupled-clock system due to a given pacemaker mutation may provide new insights into the changes in physiological processes in health and disease and support the design of new drug therapeutics for treating cardiac conditions.
Keywords: Arrhythmia; Funny current; Protein kinase A
The sinoatrial node consists of hundreds of pacemaker cells that initiate the heartbeat. Evidence has shown that pacemaker cell function is orchestrated not only by one molecule, but through molecules on the membrane and on the sarcoplasmic reticulum that are coupled by Ca2+ and post-translation modification signaling (reviewed in ). These molecules and their associated coupling nodes create the coupled-clock system that controls pacemaker function. Both experimental [2,3] and computational [4-6] evidence confirm the theory that any change in the function of any membrane or intracellular molecule should indirectly affect the function of the other molecules, and that the state of the ensemble of molecules should determine the pacemaker cells' beating rate. With the recent advances in gene research and the ability to identify mutations in membrane and intracellular molecules, mutations have been associated with several cardiac diseases [7,8]. Several groups have identified mutations in pacemaker cells involved in either bradycardia or tachycardia. Hategan et al.  reported that the HCN4 mutation c.1737+1G>T leads to bradycardia, which they interpreted to exist only by reduction in If through altered cAMP binding to HCN4. Similarly, Biel et al. [10 ] reported that the HCN4 mutation V492F leads to Brugada syndrome. The HEK293 cell line that expressed this mutation showed that If was responsive to cAMP, but required a more negative voltage for activation. These authors also concluded that "modulation of HCN4 activity could be the cause of the diagnosed cardiac abnormality". Finally, Duhme et al. have shown that the HCN4 mutation K530N is associated with ventricular tachyarrhythmia. The HEK293 cell line that expressed this mutation showed a shift in the half- maximal activation voltage of If. The authors concluded that "f-channel dysfunction contributes to the development of a trial tachyarrhythmia". However, mutation in HCN4 also alters other mechanisms of the coupled-clock system, which together change the heart rhythm [3,4,11]. At the single cell level, experimental and computational evidence have shown that blocking If by ivabradine increases the beating interval  and beating rate variability , not only through the direct effect of the If current, but through changes in Ca2+ signaling and INCX. Further computational evidence has shown that mutations that increase cAMP binding to HCN4 or alter V lead to tachycardia and bradycardia, respectively, by the afferent mechanisms and changes in post-translation modification signaling . Thus, both the direct effect on the mutant HCN4 and the indirect effect on other coupled-clock molecules lead to either bradycardia or tachycardia.
Not only have mutations in HCN4 been associated with bradycardia or tachycardia. Glukhov et al.  have shown that mutations in Calsequestrin 2 lead to loss of pacemaker function. The authors concluded that mutations in Calsequestrin 2 lead to fibrosis and altered Ca2+ signaling. Additionally, the Gómez lab has shown that mutations in the ryanodine channel (either R4496C or R420Q) are involved in catecholaminergic polymorphic ventricular tachycardia [13,14]. Although, both groups explored the mutation in one molecule, in contrast to the former groups they documented other altered mechanisms that together led to arrhythmogenic episodes. Similar to the HCN4 case, mutation in intracellular molecules also alter other mechanisms of the coupled-clock system, which together change the heart rhythm.
There is no "one important molecular determinant of heart rate regulation," but rather interaction among coupled-clock molecules, which define the heart rate and rhythm. Direct pharmacological treatments that affect cAMP binding to HCN4 or restore If do not exist. Similarly, drugs to compensate for the loss of Calsequestrin 2 or efficiently restore ryanodine function do not exist. However, it may be possible to restore the pacemaker function by using drugs that will alter other pacemaker clock molecules or coupling nodes, thus re-establishing the normal coupling between the two pacemaker clocks.
The work was supported by the NSFC-ISF Joint Research Program, No. 398/14 (Y.Y), the Israel Ministry of Science (Y.Y), an Aly-Kaufman Postdoctoral Fellowship (JB), and The Center for Absorption in Science, Ministry of Immigrant Absorption, and State of Israel (JB).
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