Dual activation of phosphodiesterases 3 and 4 regulates basal spontaneous beating rate of cardiac pacemaker cells: Role of compartmentalization?

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

Research output: Contribution to journalReview articlepeer-review

Abstract

Spontaneous firing of sinoatrial (SA) node cells (SANCs) is regulated by cyclic adenosine monophosphate (cAMP)-mediated, protein kinase A (PKA)-dependent (cAMP/PKA) local subsarcolemmal Ca2+ releases (LCRs) from ryanodine receptors (RyR). The LCRs occur during diastolic depolarization (DD) and activate an inward Na+/Ca2+ exchange current that accelerates the 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 SANCs. The cAMP-degrading PDE1, PDE3, and PDE4 represent major PDE activities in rabbit SANC, and PDE inhibition by 3-isobutyl-1-methylxanthine (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 a synergistic effect hastening the spontaneous SANC beating rate by ∼50%. Here, we describe the expression and distribution of different PDE subtypes within rabbit SANCs, 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 striated patterns inside SANCs strongly suggests that PDE-dependent regulation of cAMP/PKA signaling might be executed at the local level; this idea, however, requires further verification.

Original languageEnglish (US)
Article number1301
JournalFrontiers in Physiology
Volume9
Issue numberOCT
DOIs
StatePublished - Oct 9 2018
Externally publishedYes

Keywords

  • L-type Ca2+ channel
  • PKA phosphorylation
  • Phosphodiesterases
  • Sarco(endo)plasmic reticulum calcium ATPase
  • Sarcoplasmic reticulum
  • Sinoatrial node cells

ASJC Scopus subject areas

  • Physiology
  • Physiology (medical)

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