Positive Feedback Mechanisms among Local Ca Releases, NCX, and ICaL Ignite Pacemaker Action Potentials

Alexey E. Lyashkov, Joachim Beahr, Edward Lakatta, Yael Yaniv, Victor A. Maltsev

Research output: Contribution to journalArticle

Abstract

Recent data suggest that cardiac pacemaker cell function is determined by numerous time-, voltage-, and Ca-dependent interactions of cell membrane electrogenic proteins (M-clock) and intracellular Ca cycling proteins (Ca-clock), forming a coupled-clock system. Many aspects of the coupled-clock system, however, remain underexplored. The key players of the system are Ca release channels (ryanodine receptors), generating local Ca releases (LCRs) from sarcoplasmic reticulum, electrogenic Na/Ca exchanger (NCX) current, and L-type Ca current (ICaL). We combined numerical model simulations with experimental simultaneous recordings of action potentials (APs) and Ca to gain further insight into the complex interactions within the system. Our simulations revealed a positive feedback mechanism, dubbed AP ignition, which accelerates the diastolic depolarization (DD) to reach AP threshold. The ignition phase begins when LCRs begin to occur and the magnitude of inward NCX current begins to increase. The NCX current, together with funny current and T-type Ca current accelerates DD, bringing the membrane potential to ICaL activation threshold. During the ignition phase, ICaL-mediated Ca influx generates more LCRs via Ca-induced Ca release that further activates inward NCX current, creating a positive feedback. Simultaneous recordings of membrane potential and confocal Ca images support the model prediction of the positive feedback among LCRs and ICaL, as diastolic LCRs begin to occur below and continue within the voltage range of ICaL activation. The ignition phase onset (identified within the fine DD structure) begins when DD starts to notably accelerate (∼0.15 V/s) above the recording noise. Moreover, the timing of the ignition onset closely predicted the duration of each AP cycle in the basal state, in the presence of autonomic receptor stimulation, and in response to specific inhibition of either the M-clock or Ca-clock, thus indicating general importance of the new coupling mechanism for regulation of the pacemaker cell cycle duration, and ultimately the heart rate.

Original languageEnglish (US)
Pages (from-to)1176-1189
Number of pages14
JournalBiophysical Journal
Volume114
Issue number5
DOIs
StatePublished - Mar 13 2018
Externally publishedYes

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Action Potentials
Membrane Potentials
Ryanodine Receptor Calcium Release Channel
Sarcoplasmic Reticulum
Noise
Cell Cycle
Membrane Proteins
Heart Rate
Proteins

ASJC Scopus subject areas

  • Biophysics

Cite this

Positive Feedback Mechanisms among Local Ca Releases, NCX, and ICaL Ignite Pacemaker Action Potentials. / Lyashkov, Alexey E.; Beahr, Joachim; Lakatta, Edward; Yaniv, Yael; Maltsev, Victor A.

In: Biophysical Journal, Vol. 114, No. 5, 13.03.2018, p. 1176-1189.

Research output: Contribution to journalArticle

Lyashkov, Alexey E. ; Beahr, Joachim ; Lakatta, Edward ; Yaniv, Yael ; Maltsev, Victor A. / Positive Feedback Mechanisms among Local Ca Releases, NCX, and ICaL Ignite Pacemaker Action Potentials. In: Biophysical Journal. 2018 ; Vol. 114, No. 5. pp. 1176-1189.
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