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Front. Physiol. | doi: 10.3389/fphys.2018.01301

Dual Activation of Phosphodiesterases 3 and 4 Regulates Basal Spontaneous Beating Rate of Cardiac Pacemaker Cells: Role of Compartmentalization?

 Tatiana M. Vinogradova1, 2, 3*, Evgeny Kobrinsky1, 2, 3 and  Edward G. Lakatta1, 2, 3
  • 1National Institute on Aging (NIA), United States
  • 2National Institutes of Health (NIH), United States
  • 3Intramural Research Program (NIH), United States

Spontaneous firing of sinoatrial (SA) node cells (SANC) is regulated by cAMP-mediated, PKA-dependent (cAMP/PKA) local subsarcolemmal Ca2+releases (LCRs) from ryanodine receptors (RyR). LCRs occur during diastolic depolarization (DD) and activate an inward Na+/Ca2+ exchange current that accelerates DD rate prompting the next action potential (AP). Basal phosphodiesterases (PDEs) activation degrades cAMP, reduces basal cAMP/PKA-dependent phosphorylation and suppresses normal spontaneous firing of SANC. cAMP-degrading PDE1, PDE3 and PDE4 represent major PDE activities in rabbit SANC, and PDE inhibition by IBMX increases spontaneous firing of SANC by ~50%. Though inhibition of single PDE1-PDE4 only moderately increases spontaneous SANC firing, dual PDE3+PDE4 inhibition produces synergistic effect hastening spontaneous SANC beating rate by ~50%. Here we describe expression and distribution of different PDE subtypes within rabbit SANC, several specific targets (L-type Ca2+channels and phospholamban) regulated by basal concurrent PDE3+PDE4 activation and critical importance of RyR Ca2+releases for PDE-dependent regulation of spontaneous SANC firing. Colocalization of PDE3 and PDE4 beneath sarcolemma or in straited patterns inside SANC strongly suggests that PDE-dependent regulation of cAMP/PKA signaling might be executed at the local level; this idea, however, requires further verification.

Keywords: Sinoatrial node cells, Phosphodieserases, PKA phosphorylation, L-type Ca2+ channel, Sarcoplasmic Reticulum, SERCA (sarco(endo)plasmic reticulum Calcium ATPase)

Received: 14 Jun 2018; Accepted: 29 Aug 2018.

Edited by:

Alexey V. Glukhov, University of Wisconsin System, United States

Reviewed by:

Stefano Morotti, University of California, Davis, United States
Robert A. Rose, University of Calgary, Canada  

Copyright: © 2018 Vinogradova, Kobrinsky and Lakatta. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

* Correspondence: Dr. Tatiana M. Vinogradova, National Institute on Aging (NIA), Bethesda, 20892, Maryland, United States, vinogradovat@grc.nia.nih.gov