Sinoatrial Node Structure, Mechanics, Electrophysiology and the Chronotropic Response to Stretch in Rabbit and Mouse

Macdonald, Eilidh; Madl, Josef; Greiner, Joachim; Ramadan, Ahmed F.; Wells, Sarah; Torrente, Angelo G.; Kohl, Peter; Rog-Zielinska, Eva A.; Quinn, T. Alexander

doi:10.3389/fphys.2020.00809

Cited by 30 publications

(22 citation statements)

References 65 publications

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“…It is also now recognized that the anatomical SAN includes significant populations of fibroblasts [ 78 , 79 ]. These fibroblasts have the potential to form insulating barriers that alter conduction speed and pathways, as well as to serve as significant current sources through release of paracrine substances in response to the phasic stretch associated with the heart beat [ 80 ].…”

Section: Discussionmentioning

confidence: 99%

Physiological Roles of the Rapidly Activated Delayed Rectifier K+ Current in Adult Mouse Heart Primary Pacemaker Activity

Wei

Clark

Giles

et al. 2021

IJMS

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Robust, spontaneous pacemaker activity originating in the sinoatrial node (SAN) of the heart is essential for cardiovascular function. Anatomical, electrophysiological, and molecular methods as well as mathematical modeling approaches have quite thoroughly characterized the transmembrane fluxes of Na+, K+ and Ca2+ that produce SAN action potentials (AP) and ‘pacemaker depolarizations’ in a number of different in vitro adult mammalian heart preparations. Possible ionic mechanisms that are responsible for SAN primary pacemaker activity are described in terms of: (i) a Ca2+-regulated mechanism based on a requirement for phasic release of Ca2+ from intracellular stores and activation of an inward current-mediated by Na+/Ca2+ exchange; (ii) time- and voltage-dependent activation of Na+ or Ca2+ currents, as well as a cyclic nucleotide-activated current, If; and/or (iii) a combination of (i) and (ii). Electrophysiological studies of single spontaneously active SAN myocytes in both adult mouse and rabbit hearts consistently reveal significant expression of a rapidly activating time- and voltage-dependent K+ current, often denoted IKr, that is selectively expressed in the leading or primary pacemaker region of the adult mouse SAN. The main goal of the present study was to examine by combined experimental and simulation approaches the functional or physiological roles of this K+ current in the pacemaker activity. Our patch clamp data of mouse SAN myocytes on the effects of a pharmacological blocker, E4031, revealed that a rapidly activating K+ current is essential for action potential (AP) repolarization, and its deactivation during the pacemaker potential contributes a small but significant component to the pacemaker depolarization. Mathematical simulations using a murine SAN AP model confirm that well known biophysical properties of a delayed rectifier K+ current can contribute to its role in generating spontaneous myogenic activity.

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Section: Discussionmentioning

confidence: 99%

Physiological Roles of the Rapidly Activated Delayed Rectifier K+ Current in Adult Mouse Heart Primary Pacemaker Activity

Wei

Clark

Giles

et al. 2021

IJMS

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“…Interestingly, besides ANO1 and ClCA2, all the aforementioned ion channels affected by mechanical stress have been found to associate with caveolae, which are abundantly expressed in SAN cells ( 5 , 124 , 125 ) and are known to mediate cellular response to mechanical stress by reserving “extra” cell membrane to buffer mechanical forces and contribute to cell volume regulation ( 126 – 128 ). Caveolae are small, 50- to 100-nm omega-shaped membrane invaginations of the plasma membrane enriched by sphingolipids, cholesterol, cavin proteins, and caveolin proteins.…”

Section: Caveolae-mediated Ion Channel Mechanosensitivitymentioning

confidence: 99%

“…IP 3 Rs are another type of SR Ca 2+ release channels, which are activated by IP 3 through the hydrolysis of phosphatidylinositol-( 4 , 5 )-bisphosphate by phospholipase C and thus may also contribute to the LCR generation via hypersensitization of RyRs. They are highly abundant in atrial and SAN myocytes ( 166 – 168 ), and recent studies demonstrated that this signaling pathway might be confined within specific microdomains, including lipid rafts and dorsal ruffles ( 169 ).…”

Section: Mechanochemical Signal Transductionmentioning

confidence: 99%

“…SAN response to altered hemodynamic load is described via the Bainbridge response: an increase in heart rate upon right atrial pressure/volume increase, which may help in matching cardiac output to venous return ( 1 ). SAN mechanosensitivity and associated changes in pacemaker activity have been demonstrated at multiple levels, including isolated heart ( 2 , 3 ) as well as in isolated SAN cells ( 4 ), and have been linked to mechanosensitive mechanisms ( 5 , 6 ) intrinsic to pacemaker cells ( 7 ). In this review, we summarize the emerging understanding of cellular and molecular mechanisms that could be involved in SAN mechanosensing and pacemaker rate attenuation.…”

Section: Introductionmentioning

confidence: 99%

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Electrophysiological and Molecular Mechanisms of Sinoatrial Node Mechanosensitivity

Turner

Chen

Mesirca

et al. 2021

Front. Cardiovasc. Med.

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The understanding of the electrophysiological mechanisms that underlie mechanosensitivity of the sinoatrial node (SAN), the primary pacemaker of the heart, has been evolving over the past century. The heart is constantly exposed to a dynamic mechanical environment; as such, the SAN has numerous canonical and emerging mechanosensitive ion channels and signaling pathways that govern its ability to respond to both fast (within second or on beat-to-beat manner) and slow (minutes) timescales. This review summarizes the effects of mechanical loading on the SAN activity and reviews putative candidates, including fast mechanoactivated channels (Piezo, TREK, and BK) and slow mechanoresponsive ion channels [including volume-regulated chloride channels and transient receptor potential (TRP)], as well as the components of mechanochemical signal transduction, which may contribute to SAN mechanosensitivity. Furthermore, we examine the structural foundation for both mechano-electrical and mechanochemical signal transduction and discuss the role of specialized membrane nanodomains, namely, caveolae, in mechanical regulation of both membrane and calcium clock components of the so-called coupled-clock pacemaker system responsible for SAN automaticity. Finally, we emphasize how these mechanically activated changes contribute to the pathophysiology of SAN dysfunction and discuss controversial areas necessitating future investigations. Though the exact mechanisms of SAN mechanosensitivity are currently unknown, identification of such components, their impact into SAN pacemaking, and pathological remodeling may provide new therapeutic targets for the treatment of SAN dysfunction and associated rhythm abnormalities.

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“…Thus, the important role of TREK-1 in the function of the sinoatrial and/or atrioventricular nodes is established, however, the contribution of this channel to the local stretch-induced changes of the heart rate and atrioventricular conduction velocity is not known. There is a substantial interspecies difference; the heart rate is increased by the local stretch of the sinoatrial node in rabbits and most probably in humans, but it is not reproducibly changed in mice [138,146]. TREK-1 activation would counter this effect in the species, where the heart rate is increased by the local stretch of the sinoatrial node.…”

Section: Mechanical Activation Of K 2p Channels In the Heartmentioning

confidence: 99%

Negative Influence by the Force: Mechanically Induced Hyperpolarization via K2P Background Potassium Channels

Lengyel

Enyedi

Czirják

2021

IJMS

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The two-pore domain K2P subunits form background (leak) potassium channels, which are characterized by constitutive, although not necessarily constant activity, at all membrane potential values. Among the fifteen pore-forming K2P subunits encoded by the KCNK genes, the three members of the TREK subfamily, TREK-1, TREK-2, and TRAAK are mechanosensitive ion channels. Mechanically induced opening of these channels generally results in outward K+ current under physiological conditions, with consequent hyperpolarization and inhibition of membrane potential-dependent cellular functions. In the past decade, great advances have been made in the investigation of the molecular determinants of mechanosensation, and members of the TREK subfamily have emerged among the best-understood examples of mammalian ion channels directly influenced by the tension of the phospholipid bilayer. In parallel, the crucial contribution of mechano-gated TREK channels to the regulation of membrane potential in several cell types has been reported. In this review, we summarize the general principles underlying the mechanical activation of K2P channels, and focus on the physiological roles of mechanically induced hyperpolarization.

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Sinoatrial Node Structure, Mechanics, Electrophysiology and the Chronotropic Response to Stretch in Rabbit and Mouse

Cited by 30 publications

References 65 publications

Physiological Roles of the Rapidly Activated Delayed Rectifier K+ Current in Adult Mouse Heart Primary Pacemaker Activity

Physiological Roles of the Rapidly Activated Delayed Rectifier K+ Current in Adult Mouse Heart Primary Pacemaker Activity

Electrophysiological and Molecular Mechanisms of Sinoatrial Node Mechanosensitivity

Negative Influence by the Force: Mechanically Induced Hyperpolarization via K2P Background Potassium Channels

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