AUTHOR=Turner Daniel , Kang Chen , Mesirca Pietro , Hong Juan , Mangoni Matteo E. , Glukhov Alexey V. , Sah Rajan 

TITLE=Electrophysiological and Molecular Mechanisms of Sinoatrial Node Mechanosensitivity

JOURNAL=Frontiers in Cardiovascular Medicine

VOLUME=Volume 8 - 2021

YEAR=2021

URL=https://www.frontiersin.org/journals/cardiovascular-medicine/articles/10.3389/fcvm.2021.662410

DOI=10.3389/fcvm.2021.662410

ISSN=2297-055X

ABSTRACT=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 of such, the SAN has numerous canonical and emerging mechano-sensitive ion channels and signaling pathways that govern its ability to respond on both fast (within second or on beat-to-beat manner) and a slow (minutes) basis. This review summarizes the effects of mechanical loading on the SAN activity and reviews putative candidates, including fast mechano-activated channels (Piezo, TREK, BK) and slow mechano-responsive ion channels (including volume-regulated chloride channels and TRP), as well as the components of mechano-chemical signal transduction, that may contribute to SAN mechanosensitivity. Furthermore, we examine the structural foundation for both mechano-electrical and mechano-chemical signal transduction and discuss the role of specialized membrane nanodomains, namely caveolae, in mechanical regulation of both membrane and calcium clock components of 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.