AUTHOR=Vinogradova Tatiana M. , Kobrinsky Evgeny , Lakatta Edward G. 

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

JOURNAL=Frontiers in Physiology

VOLUME=Volume 9 - 2018

YEAR=2018

URL=https://www.frontiersin.org/journals/physiology/articles/10.3389/fphys.2018.01301

DOI=10.3389/fphys.2018.01301

ISSN=1664-042X

ABSTRACT=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.