The Experts below are selected from a list of 297 Experts worldwide ranked by ideXlab platform
Vadim V. Fedorov - One of the best experts on this subject based on the ideXlab platform.
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Two‐Pore K+ Channel TREK‐1 Regulates Sinoatrial Node Membrane Excitability
Journal of the American Heart Association, 2016Co-Authors: Sathya D Unudurthi, Lan Qian, Foued Amari, Birce Onal, Xiangqiong Wu, Michael A Makara, Sakima A Smith, Jedidiah S Snyder, Ning Li, Vadim V. FedorovAbstract:Background Two‐pore K+ channels have emerged as potential targets to selectively regulate cardiac cell membrane excitability; however, lack of specific inhibitors and relevant animal models has impeded the effort to understand the role of 2‐pore K+ channels in the heart and their potential as a therapeutic target. The objective of this study was to determine the role of mechanosensitive 2‐pore K+ channel family member TREK‐1 in control of cardiac excitability. Methods and Results Cardiac‐specific TREK‐1–deficient mice (αMHC‐ Kcnk f/f) were generated and found to have a prevalent Sinoatrial phenotype characterized by bradycardia with frequent episodes of sinus pause following stress. Action potential measurements from isolated αMHC‐ Kcnk2 f/f Sinoatrial Node cells demonstrated decreased background K+ current and abnormal Sinoatrial cell membrane excitability. To identify novel pathways for regulating TREK‐1 activity and Sinoatrial Node excitability, mice expressing a truncated allele of the TREK‐1–associated cytoskeletal protein βIV‐spectrin ( qv 4J mice) were analyzed and found to display defects in cell electrophysiology as well as loss of normal TREK‐1 membrane localization. Finally, the βIV‐spectrin/TREK‐1 complex was found to be downregulated in the right atrium from a canine model of Sinoatrial Node dysfunction and in human cardiac disease. Conclusions These findings identify a TREK‐1–dependent pathway essential for normal Sinoatrial Node cell excitability that serves as a potential target for selectively regulating Sinoatrial Node cell function.
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two pore k channel trek 1 regulates Sinoatrial Node membrane excitability
Journal of the American Heart Association, 2016Co-Authors: Sathya D Unudurthi, Lan Qian, Foued Amari, Birce Onal, Xiangqiong Wu, Michael A Makara, Sakima A Smith, Jedidiah S Snyder, Ning Li, Vadim V. FedorovAbstract:Background Two‐pore K+ channels have emerged as potential targets to selectively regulate cardiac cell membrane excitability; however, lack of specific inhibitors and relevant animal models has impeded the effort to understand the role of 2‐pore K+ channels in the heart and their potential as a therapeutic target. The objective of this study was to determine the role of mechanosensitive 2‐pore K+ channel family member TREK‐1 in control of cardiac excitability. Methods and Results Cardiac‐specific TREK‐1–deficient mice (αMHC‐ Kcnk f/f) were generated and found to have a prevalent Sinoatrial phenotype characterized by bradycardia with frequent episodes of sinus pause following stress. Action potential measurements from isolated αMHC‐ Kcnk2 f/f Sinoatrial Node cells demonstrated decreased background K+ current and abnormal Sinoatrial cell membrane excitability. To identify novel pathways for regulating TREK‐1 activity and Sinoatrial Node excitability, mice expressing a truncated allele of the TREK‐1–associated cytoskeletal protein βIV‐spectrin ( qv 4J mice) were analyzed and found to display defects in cell electrophysiology as well as loss of normal TREK‐1 membrane localization. Finally, the βIV‐spectrin/TREK‐1 complex was found to be downregulated in the right atrium from a canine model of Sinoatrial Node dysfunction and in human cardiac disease. Conclusions These findings identify a TREK‐1–dependent pathway essential for normal Sinoatrial Node cell excitability that serves as a potential target for selectively regulating Sinoatrial Node cell function.
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postganglionic nerve stimulation induces temporal inhibition of excitability in rabbit Sinoatrial Node
American Journal of Physiology-heart and Circulatory Physiology, 2006Co-Authors: Vadim V. Fedorov, Halina Dobrzynski, Leonid V. Rosenshtraukh, William J Hucker, Igor R EfimovAbstract:Vagal stimulation results in complex changes of pacemaker excitability in the Sinoatrial Node (SAN). To investigate the vagal effects in the rabbit SAN, we used optical mapping, which is the only t...
Mark R. Boyett - One of the best experts on this subject based on the ideXlab platform.
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The Sinoatrial Node Is Still Setting the Pace 100 Years After its Discovery
Circulation Research, 2007Co-Authors: Mark R. Boyett, Halina DobrzynskiAbstract:See related article, pages 1605–1614 The mammalian Sinoatrial Node, the pacemaker of the heart, was discovered 100 years ago in the countryside of Kent (UK) in “a cosy, squat, red-roofed farm-house, embowered in creepers, separated from the road by a richly stocked garden” with “a horse going round and round winding up a huge bucket from a very deep well” and a “farmyard, filled with healthy farmyard manure”.1 Arthur Keith (later Sir Arthur) had converted the drawing room into a laboratory and recruited the assistance of Martin Flack, the son of the local butcher and grocer and a young medical student at the time.1 One evening when Keith and his wife, Celia, returned from a bicycle ride, Flack showed him a “wonderful structure” he had discovered in the heart of a mole (perhaps caught on the farm?)—so was discovered the Sinoatrial Node. Keith and Flack published the discovery of the Sinoatrial Node in 1907 in the Journal of Anatomy and Physiology .2 Curiously, only a few years later, Keith was to become embroiled in one of the biggest scientific scandals of all time, ‘Piltdown man’, a fraudulent ‘missing link’. Now 100 years after the discovery of the Sinoatrial Node, we are still making new discoveries about the workings of the Sinoatrial Node as shown by the paper from Ju and Allen and colleagues in this issue of Circulation Research —the Sinoatrial Node is still setting the pace!3 In the 1970s and 1980s a flurry of voltage clamp studies, first on multicellular preparations of Sinoatrial Node tissue and then on isolated Sinoatrial Node cells, appeared to establish the mechanism of pacemaking in the Sinoatrial Node.4 At this time, pacemaking was primarily thought to be result of the decay of delayed rectifier K+ current (K …
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ageing related changes of connexins and conduction within the Sinoatrial Node
The Journal of Physiology, 2004Co-Authors: Sandra A Jones, Matthew K. Lancaster, Mark R. BoyettAbstract:Clinical studies have shown that Sinoatrial Node dysfunction occurs at the highest incidence in the elderly population. Guinea-pigs were studied throughout their lifespan (i.e. birth to 38 months) to investigate the possible mechanism leading to nodal dysfunction. Using immunofluorescence with confocal microscopy, Cx43 protein expression was shown at birth to be present throughout the Sinoatrial Node and atrial muscle, however, at one month Cx43 protein was not expressed in the centre of the Sinoatrial Node. Throughout the remainder of the animal's lifespan the area of tissue lacking Cx43 protein progressively increased. Western blot provided verification by quantitative analysis that Cx43 protein expression within the Sinoatrial Node decreased with age; however, the expression of other cardiac connexins, Cx40 and Cx45, did not differ with age. Analysis of conduction maps showing propagation of the action potential across the Sinoatrial Node, from the initiation point to the crista terminalis, found that the action potential conduction time taken and conduction distance increased proportionally with age; conversely the conduction velocity decreased with age. We have shown ageing induces degenerative changes in action potential conduction, contributed to by the observed loss of Cx43 protein. Our data identify Cx43 as a potential therapeutic target for quashing the age-related deterioration of the cardiac pacemaker.
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STRUCTURE-FUNCTION RELATIONSHIPS OF THE Sinoatrial Node
International Journal of Bifurcation and Chaos, 2003Co-Authors: Halina Dobrzynski, Henggui Zhang, Sally Wright, Arun V. Holden, Mark R. BoyettAbstract:The Sinoatrial Node, the pacemaker of the heart, is a structurally and functionally complex and heterogeneous structure. Histology, immunohistochemistry, electrophysiology and mathematical modeling of the Sinoatrial Node are reviewed to reveal the structure-function relationships of the Sinoatrial Node. It is argued that contact between the Sinoatrial Node and surrounding atrial muscle is limited to permit driving of the atrial muscle by the Sinoatrial Node but not suppression of the Sinoatrial Node by the atrial muscle (which is more hyperpolarized). It is argued that a protective conduction block zone on one side of the Sinoatrial Node is the result of a lack of myocytes. Finally, it is argued that the cellular organization of the Sinoatrial Node is best described by the gradient model.
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one dimensional rabbit Sinoatrial Node models benefits and limitations
Journal of Cardiovascular Electrophysiology, 2003Co-Authors: Alan Garny, Mark R. Boyett, Peter Kohl, Peter Hunter, Denis NobleAbstract:Introduction: Cardiac multicellular modeling has traditionally focused on ventricular electromechanics. More recently, models of the atria have started to emerge, and there is much interest in addressing Sinoatrial Node structure and function. Methods and Results: We implemented a variety of one-dimensional Sinoatrial models consisting of descriptions of central, transitional, and peripheral Sinoatrial Node cells, as well as rabbit or human atrial cells. These one-dimensional models were implemented using CMISS on an SGI® Origin® 2000 supercomputer. Intercellular coupling parameters recorded in experimental studies on Sinoatrial Node and atrial cell-pairs under-represent the electrotonic interactions that any cardiomyocyte would have in a multidimensional setting. Unsurprisingly, cell-to-cell coupling had to be scaled-up (by a factor of 5) in order to obtain a stable leading pacemaker site in the Sinoatrial Node center. Further critical parameters include the gradual increase in intercellular coupling from Sinoatrial Node center to periphery, and the presence of electrotonic interaction with atrial cells. Interestingly, the electrotonic effect of the atrium on Sinoatrial Node periphery is best described as opposing depolarization, rather than necessarily hyperpolarizing, as often assumed. Conclusion: Multicellular one-dimensional models of Sinoatrial Node and atrium can provide useful insight into the origin and spread of normal cardiac excitation. They require larger than “physiologic” intercellular conductivities in order to make up for a lack of “anatomical” spatial scaling. Multicellular models for more in-depth quantitative studies will require more realistic anatomico-physiologic properties. (J Cardiovasc Electrophysiol, Vol. 14, pp. S121-S132, October 2003, Suppl.)
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Sophisticated architecture is required for the Sinoatrial Node to perform its normal pacemaker function
Journal of Cardiovascular Electrophysiology, 2003Co-Authors: Mark R. Boyett, Halina Dobrzynski, S. A. Jones, Matthew K. Lancaster, Haruo Honjo, Itsuo KodamaAbstract:The heart's pacemaker, the Sinoatrial Node, does not consist of a group of uniform Sinoatrial Node cells embedded in atrial muscle. Instead, it is a heterogeneous tissue with multiple cell types and a complex structure. Evidence suggests that from the periphery to the center of the Sinoatrial Node, there is a gradient in action potential shape, pacemaking, ionic current densities, connexin expression, Ca2+ handling, myofilament density, and cell size. This complexity may be necessary for the Sinoatrial Node to pacemake under diverse conditions, drive the more hyperpolarized atrial muscle, and resist proarrhythmic perturbations.
Birce Onal - One of the best experts on this subject based on the ideXlab platform.
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Two‐Pore K+ Channel TREK‐1 Regulates Sinoatrial Node Membrane Excitability
Journal of the American Heart Association, 2016Co-Authors: Sathya D Unudurthi, Lan Qian, Foued Amari, Birce Onal, Xiangqiong Wu, Michael A Makara, Sakima A Smith, Jedidiah S Snyder, Ning Li, Vadim V. FedorovAbstract:Background Two‐pore K+ channels have emerged as potential targets to selectively regulate cardiac cell membrane excitability; however, lack of specific inhibitors and relevant animal models has impeded the effort to understand the role of 2‐pore K+ channels in the heart and their potential as a therapeutic target. The objective of this study was to determine the role of mechanosensitive 2‐pore K+ channel family member TREK‐1 in control of cardiac excitability. Methods and Results Cardiac‐specific TREK‐1–deficient mice (αMHC‐ Kcnk f/f) were generated and found to have a prevalent Sinoatrial phenotype characterized by bradycardia with frequent episodes of sinus pause following stress. Action potential measurements from isolated αMHC‐ Kcnk2 f/f Sinoatrial Node cells demonstrated decreased background K+ current and abnormal Sinoatrial cell membrane excitability. To identify novel pathways for regulating TREK‐1 activity and Sinoatrial Node excitability, mice expressing a truncated allele of the TREK‐1–associated cytoskeletal protein βIV‐spectrin ( qv 4J mice) were analyzed and found to display defects in cell electrophysiology as well as loss of normal TREK‐1 membrane localization. Finally, the βIV‐spectrin/TREK‐1 complex was found to be downregulated in the right atrium from a canine model of Sinoatrial Node dysfunction and in human cardiac disease. Conclusions These findings identify a TREK‐1–dependent pathway essential for normal Sinoatrial Node cell excitability that serves as a potential target for selectively regulating Sinoatrial Node cell function.
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two pore k channel trek 1 regulates Sinoatrial Node membrane excitability
Journal of the American Heart Association, 2016Co-Authors: Sathya D Unudurthi, Lan Qian, Foued Amari, Birce Onal, Xiangqiong Wu, Michael A Makara, Sakima A Smith, Jedidiah S Snyder, Ning Li, Vadim V. FedorovAbstract:Background Two‐pore K+ channels have emerged as potential targets to selectively regulate cardiac cell membrane excitability; however, lack of specific inhibitors and relevant animal models has impeded the effort to understand the role of 2‐pore K+ channels in the heart and their potential as a therapeutic target. The objective of this study was to determine the role of mechanosensitive 2‐pore K+ channel family member TREK‐1 in control of cardiac excitability. Methods and Results Cardiac‐specific TREK‐1–deficient mice (αMHC‐ Kcnk f/f) were generated and found to have a prevalent Sinoatrial phenotype characterized by bradycardia with frequent episodes of sinus pause following stress. Action potential measurements from isolated αMHC‐ Kcnk2 f/f Sinoatrial Node cells demonstrated decreased background K+ current and abnormal Sinoatrial cell membrane excitability. To identify novel pathways for regulating TREK‐1 activity and Sinoatrial Node excitability, mice expressing a truncated allele of the TREK‐1–associated cytoskeletal protein βIV‐spectrin ( qv 4J mice) were analyzed and found to display defects in cell electrophysiology as well as loss of normal TREK‐1 membrane localization. Finally, the βIV‐spectrin/TREK‐1 complex was found to be downregulated in the right atrium from a canine model of Sinoatrial Node dysfunction and in human cardiac disease. Conclusions These findings identify a TREK‐1–dependent pathway essential for normal Sinoatrial Node cell excitability that serves as a potential target for selectively regulating Sinoatrial Node cell function.
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cycle length restitution in Sinoatrial Node cells a theory for understanding spontaneous action potential dynamics
PLOS ONE, 2014Co-Authors: Birce Onal, Patric Glynn, Thomas J HundAbstract:Normal heart rhythm (sinus rhythm) is governed by the Sinoatrial Node, a specialized and highly heterogeneous collection of spontaneously active myocytes in the right atrium. Sinoatrial Node dysfunction, characterized by slow and/or asynchronous pacemaker activity and even failure, is associated with cardiovascular disease (e.g. heart failure, atrial fibrillation). While tremendous progress has been made in understanding the molecular and ionic basis of automaticity in Sinoatrial Node cells, the dynamics governing Sinoatrial Nodel cell synchrony and overall pacemaker function remain unclear. Here, a well-validated computational model of the mouse Sinoatrial Node cell is used to test the hypothesis that Sinoatrial Node cell dynamics reflect an inherent restitution property (cycle length restitution) that may give rise to a wide range of behavior from regular periodicity to highly complex, irregular activation. Computer simulations are performed to determine the cycle length restitution curve in the computational model using a newly defined voltage pulse protocol. The ability of the restitution curve to predict Sinoatrial Node cell dynamics (e.g., the emergence of irregular spontaneous activity) and susceptibility to termination is evaluated. Finally, ionic and tissue level factors (e.g. ion channel conductances, ion concentrations, cell-to-cell coupling) that influence restitution and Sinoatrial Node cell dynamics are explored. Together, these findings suggest that cycle length restitution may be a useful tool for analyzing cell dynamics and dysfunction in the Sinoatrial Node.
Sathya D Unudurthi - One of the best experts on this subject based on the ideXlab platform.
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Two‐Pore K+ Channel TREK‐1 Regulates Sinoatrial Node Membrane Excitability
Journal of the American Heart Association, 2016Co-Authors: Sathya D Unudurthi, Lan Qian, Foued Amari, Birce Onal, Xiangqiong Wu, Michael A Makara, Sakima A Smith, Jedidiah S Snyder, Ning Li, Vadim V. FedorovAbstract:Background Two‐pore K+ channels have emerged as potential targets to selectively regulate cardiac cell membrane excitability; however, lack of specific inhibitors and relevant animal models has impeded the effort to understand the role of 2‐pore K+ channels in the heart and their potential as a therapeutic target. The objective of this study was to determine the role of mechanosensitive 2‐pore K+ channel family member TREK‐1 in control of cardiac excitability. Methods and Results Cardiac‐specific TREK‐1–deficient mice (αMHC‐ Kcnk f/f) were generated and found to have a prevalent Sinoatrial phenotype characterized by bradycardia with frequent episodes of sinus pause following stress. Action potential measurements from isolated αMHC‐ Kcnk2 f/f Sinoatrial Node cells demonstrated decreased background K+ current and abnormal Sinoatrial cell membrane excitability. To identify novel pathways for regulating TREK‐1 activity and Sinoatrial Node excitability, mice expressing a truncated allele of the TREK‐1–associated cytoskeletal protein βIV‐spectrin ( qv 4J mice) were analyzed and found to display defects in cell electrophysiology as well as loss of normal TREK‐1 membrane localization. Finally, the βIV‐spectrin/TREK‐1 complex was found to be downregulated in the right atrium from a canine model of Sinoatrial Node dysfunction and in human cardiac disease. Conclusions These findings identify a TREK‐1–dependent pathway essential for normal Sinoatrial Node cell excitability that serves as a potential target for selectively regulating Sinoatrial Node cell function.
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two pore k channel trek 1 regulates Sinoatrial Node membrane excitability
Journal of the American Heart Association, 2016Co-Authors: Sathya D Unudurthi, Lan Qian, Foued Amari, Birce Onal, Xiangqiong Wu, Michael A Makara, Sakima A Smith, Jedidiah S Snyder, Ning Li, Vadim V. FedorovAbstract:Background Two‐pore K+ channels have emerged as potential targets to selectively regulate cardiac cell membrane excitability; however, lack of specific inhibitors and relevant animal models has impeded the effort to understand the role of 2‐pore K+ channels in the heart and their potential as a therapeutic target. The objective of this study was to determine the role of mechanosensitive 2‐pore K+ channel family member TREK‐1 in control of cardiac excitability. Methods and Results Cardiac‐specific TREK‐1–deficient mice (αMHC‐ Kcnk f/f) were generated and found to have a prevalent Sinoatrial phenotype characterized by bradycardia with frequent episodes of sinus pause following stress. Action potential measurements from isolated αMHC‐ Kcnk2 f/f Sinoatrial Node cells demonstrated decreased background K+ current and abnormal Sinoatrial cell membrane excitability. To identify novel pathways for regulating TREK‐1 activity and Sinoatrial Node excitability, mice expressing a truncated allele of the TREK‐1–associated cytoskeletal protein βIV‐spectrin ( qv 4J mice) were analyzed and found to display defects in cell electrophysiology as well as loss of normal TREK‐1 membrane localization. Finally, the βIV‐spectrin/TREK‐1 complex was found to be downregulated in the right atrium from a canine model of Sinoatrial Node dysfunction and in human cardiac disease. Conclusions These findings identify a TREK‐1–dependent pathway essential for normal Sinoatrial Node cell excitability that serves as a potential target for selectively regulating Sinoatrial Node cell function.
Lan Qian - One of the best experts on this subject based on the ideXlab platform.
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Two‐Pore K+ Channel TREK‐1 Regulates Sinoatrial Node Membrane Excitability
Journal of the American Heart Association, 2016Co-Authors: Sathya D Unudurthi, Lan Qian, Foued Amari, Birce Onal, Xiangqiong Wu, Michael A Makara, Sakima A Smith, Jedidiah S Snyder, Ning Li, Vadim V. FedorovAbstract:Background Two‐pore K+ channels have emerged as potential targets to selectively regulate cardiac cell membrane excitability; however, lack of specific inhibitors and relevant animal models has impeded the effort to understand the role of 2‐pore K+ channels in the heart and their potential as a therapeutic target. The objective of this study was to determine the role of mechanosensitive 2‐pore K+ channel family member TREK‐1 in control of cardiac excitability. Methods and Results Cardiac‐specific TREK‐1–deficient mice (αMHC‐ Kcnk f/f) were generated and found to have a prevalent Sinoatrial phenotype characterized by bradycardia with frequent episodes of sinus pause following stress. Action potential measurements from isolated αMHC‐ Kcnk2 f/f Sinoatrial Node cells demonstrated decreased background K+ current and abnormal Sinoatrial cell membrane excitability. To identify novel pathways for regulating TREK‐1 activity and Sinoatrial Node excitability, mice expressing a truncated allele of the TREK‐1–associated cytoskeletal protein βIV‐spectrin ( qv 4J mice) were analyzed and found to display defects in cell electrophysiology as well as loss of normal TREK‐1 membrane localization. Finally, the βIV‐spectrin/TREK‐1 complex was found to be downregulated in the right atrium from a canine model of Sinoatrial Node dysfunction and in human cardiac disease. Conclusions These findings identify a TREK‐1–dependent pathway essential for normal Sinoatrial Node cell excitability that serves as a potential target for selectively regulating Sinoatrial Node cell function.
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two pore k channel trek 1 regulates Sinoatrial Node membrane excitability
Journal of the American Heart Association, 2016Co-Authors: Sathya D Unudurthi, Lan Qian, Foued Amari, Birce Onal, Xiangqiong Wu, Michael A Makara, Sakima A Smith, Jedidiah S Snyder, Ning Li, Vadim V. FedorovAbstract:Background Two‐pore K+ channels have emerged as potential targets to selectively regulate cardiac cell membrane excitability; however, lack of specific inhibitors and relevant animal models has impeded the effort to understand the role of 2‐pore K+ channels in the heart and their potential as a therapeutic target. The objective of this study was to determine the role of mechanosensitive 2‐pore K+ channel family member TREK‐1 in control of cardiac excitability. Methods and Results Cardiac‐specific TREK‐1–deficient mice (αMHC‐ Kcnk f/f) were generated and found to have a prevalent Sinoatrial phenotype characterized by bradycardia with frequent episodes of sinus pause following stress. Action potential measurements from isolated αMHC‐ Kcnk2 f/f Sinoatrial Node cells demonstrated decreased background K+ current and abnormal Sinoatrial cell membrane excitability. To identify novel pathways for regulating TREK‐1 activity and Sinoatrial Node excitability, mice expressing a truncated allele of the TREK‐1–associated cytoskeletal protein βIV‐spectrin ( qv 4J mice) were analyzed and found to display defects in cell electrophysiology as well as loss of normal TREK‐1 membrane localization. Finally, the βIV‐spectrin/TREK‐1 complex was found to be downregulated in the right atrium from a canine model of Sinoatrial Node dysfunction and in human cardiac disease. Conclusions These findings identify a TREK‐1–dependent pathway essential for normal Sinoatrial Node cell excitability that serves as a potential target for selectively regulating Sinoatrial Node cell function.
