biostudies-literatureMazgaoker SUS-Israel Binational Science FoundationIsrael Science Foundatione202213153https://www.ebi.ac.uk/biostudies/studies/S-EPMC9674091biostudies-literatureUnknown155(1)Human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) have been used to screen and characterize drugs and to reveal mechanisms underlying cardiac diseases. However, before hiPSC-CMs can be used as a reliable experimental model, the physiological mechanisms underlying their normal function should be further explored. Accordingly, a major feature of hiPSC-CMs is automaticity, which is regulated by both Ca2+ and membrane clocks. To investigate the mechanisms coupling these clocks, we tested three hypotheses: (1) normal automaticity of spontaneously beating hiPSC-CMs is regulated by local Ca2+ releases (LCRs) and cAMP/PKA-dependent coupling of Ca2+ clock to M clock; (2) the LCR period indicates the level of crosstalk within the coupled-clock system; and (3) perturbing the actiThe Journal of general physiologycAMP-PKA signaling modulates the automaticity of human iPSC-derived cardiomyocytes.PMC9674091ISF 824/19Mazgaoker SWeiser-Bitoun IBrosh IYaniv YBinah OfalsecAMP-PKA signaling modulates the automaticity of human iPSC-derived cardiomyocytes.Human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) have been used to screen and characterize drugs and to reveal mechanisms underlying cardiac diseases. However, before hiPSC-CMs can be used as a reliable experimental model, the physiological mechanisms underlying their normal function should be further explored. Accordingly, a major feature of hiPSC-CMs is automaticity, which is regulated by both Ca2+ and membrane clocks. To investigate the mechanisms coupling these clocks, we tested three hypotheses: (1) normal automaticity of spontaneously beating hiPSC-CMs is regulated by local Ca2+ releases (LCRs) and cAMP/PKA-dependent coupling of Ca2+ clock to M clock; (2) the LCR period indicates the level of crosstalk within the coupled-clock system; and (3) perturbing the acti2023-01-01T00:00:00Z2023 Jan2025-04-22T18:28:59.371Z2025-04-06T02:27:15.993ZS-EPMC96740913638323210.1085/jgp.202213153