title: STIM1-Ca2+ signaling modulates automaticity of the mouse sinoatrial node.
abstract: Cardiac pacemaking is governed by specialized cardiomyocytes located in the sinoatrial node (SAN). SAN cells (SANCs) integrate voltage-gated currents from channels on the membrane surface (membrane clock) with rhythmic Ca(2+) release from internal Ca(2+) stores (Ca(2+) clock) to adjust heart rate to meet hemodynamic demand. Here, we report that stromal interaction molecule 1 (STIM1) and Orai1 channels, key components of store-operated Ca(2+) entry, are selectively expressed in SANCs. Cardiac-specific deletion of STIM1 in mice resulted in depletion of sarcoplasmic reticulum (SR) Ca(2+) stores of SANCs and led to SAN dysfunction, as was evident by a reduction in heart rate, sinus arrest, and an exaggerated autonomic response to cholinergic signaling. Moreover, STIM1 influenced SAN function by regulating ionic fluxes in SANCs, including activation of a store-operated Ca(2+) current, a reduction in L-type Ca(2+) current, and enhancing the activities of Na(+)/Ca(2+) exchanger. In conclusion, these studies reveal that STIM1 is a multifunctional regulator of Ca(2+) dynamics in SANCs that links SR Ca(2+) store content with electrical events occurring in the plasma membrane, thereby contributing to automaticity of the SAN.
authors.affiliation: Department of Medicine, Duke University School of Medicine, Durham, NC 27704;
authors.forename: Hengtao
authors.initials: H
authors.lastname: Zhang
authors.affiliation: Department of Medicine, Duke University School of Medicine, Durham, NC 27704;
authors.forename: Albert Y
authors.initials: AY
authors.lastname: Sun
authors.affiliation: Department of Biomedical Engineering, Duke University, Durham, NC 27708;
authors.forename: Jong J
authors.initials: JJ
authors.lastname: Kim
authors.affiliation: Department of Medicine, Duke University School of Medicine, Durham, NC 27704;
authors.forename: Victoria
authors.initials: V
authors.lastname: Graham
authors.affiliation: Department of Medicine, Duke University School of Medicine, Durham, NC 27704;
authors.forename: Elizabeth A
authors.initials: EA
authors.lastname: Finch
authors.affiliation: Department of Medicine, Duke University School of Medicine, Durham, NC 27704;
authors.forename: Igor
authors.initials: I
authors.lastname: Nepliouev
authors.affiliation: Department of Physiology, Center for BioMedical Engineering and Technology, University of Maryland School of Medicine, Baltimore, MD 21201.
authors.forename: Guiling
authors.initials: G
authors.lastname: Zhao
authors.affiliation: Department of Medicine, Duke University School of Medicine, Durham, NC 27704;
authors.forename: Tianyu
authors.initials: T
authors.lastname: Li
authors.affiliation: Department of Physiology, Center for BioMedical Engineering and Technology, University of Maryland School of Medicine, Baltimore, MD 21201.
authors.forename: W J
authors.initials: WJ
authors.lastname: Lederer
authors.affiliation: Department of Medicine, Duke University School of Medicine, Durham, NC 27704;
authors.forename: Jonathan A
authors.initials: JA
authors.lastname: Stiber
authors.affiliation: Department of Medicine, Duke University School of Medicine, Durham, NC 27704;
authors.forename: Geoffrey S
authors.initials: GS
authors.lastname: Pitt
authors.affiliation: Department of Biomedical Engineering, Duke University, Durham, NC 27708;
authors.forename: Nenad
authors.initials: N
authors.lastname: Bursac
authors.affiliation: Department of Medicine, Duke University School of Medicine, Durham, NC 27704; rosen029@mc.duke.edu.
authors.forename: Paul B
authors.initials: PB
authors.lastname: Rosenberg
mesh_terms: D000818:Animals; D002118:Calcium / Q000378:metabolism*; D015220:Calcium Channels / Q000235:genetics / Q000378:metabolism*; D020746:Calcium Channels, L-Type / Q000235:genetics / Q000378:metabolism; D020013:Calcium Signaling / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D032383:Myocytes, Cardiac / Q000166:cytology / Q000378:metabolism*; D000071740:ORAI1 Protein; D012519:Sarcoplasmic Reticulum / Q000235:genetics / Q000378:metabolism*; D012849:Sinoatrial Node / Q000166:cytology / Q000378:metabolism*; D000071737:Stromal Interaction Molecule 1
chemical_list: D015220:Calcium Channels; D020746:Calcium Channels, L-Type; D000071740:ORAI1 Protein; C520430:Orai1 protein, mouse; C100757:Stim1 protein, mouse; D000071737:Stromal Interaction Molecule 1; D002118:Calcium
keywords: SAN; STIM1; calcium; channels; pacemaker