title: An integrated mechanism of cardiomyocyte nuclear Ca(2+) signaling.
abstract: In cardiomyocytes, Ca(2+) plays a central role in governing both contraction and signaling events that regulate gene expression. Current evidence indicates that discrimination between these two critical functions is achieved by segregating Ca(2+) within subcellular microdomains: transcription is regulated by Ca(2+) release within nuclear microdomains, and excitation-contraction coupling is regulated by cytosolic Ca(2+). Accordingly, a variety of agonists that control cardiomyocyte gene expression, such as endothelin-1, angiotensin-II or insulin-like growth factor-1, share the feature of triggering nuclear Ca(2+) signals. However, signaling pathways coupling surface receptor activation to nuclear Ca(2+) release, and the phenotypic responses to such signals, differ between agonists. According to earlier hypotheses, the selective control of nuclear Ca(2+) signals by activation of plasma membrane receptors relies on the strategic localization of inositol trisphosphate receptors at the nuclear envelope. There, they mediate Ca(2+) release from perinuclear Ca(2+) stores upon binding of inositol trisphosphate generated in the cytosol, which diffuses into the nucleus. More recently, identification of such receptors at nuclear membranes or perinuclear sarcolemmal invaginations has uncovered novel mechanisms whereby agonists control nuclear Ca(2+) release. In this review, we discuss mechanisms for the selective control of nuclear Ca(2+) signals with special focus on emerging models of agonist receptor activation.
authors.affiliation: Cardiovascular and Metabolic Diseases, Innovative Medicines and Early Development, AstraZeneca R&D, Mölndal, Sweden. Electronic address: cristian.ibarra@astrazeneca.com.
authors.forename: Cristián
authors.initials: C
authors.lastname: Ibarra
authors.affiliation: Hatter Cardiovascular Institute, University College London, London, United Kingdom.
authors.forename: Jose Miguel
authors.initials: JM
authors.lastname: Vicencio
authors.affiliation: Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Manuel
authors.initials: M
authors.lastname: Varas-Godoy
authors.affiliation: Centro de Estudios Moleculares de la Célula, Facultad de Ciencias Químicas y Farmacéuticas & Facultad de Medicina, Universidad de Chile, Santiago, Chile.
authors.forename: Enrique
authors.initials: E
authors.lastname: Jaimovich
authors.affiliation: Department of Internal Medicine, Cardiology Division, University of Texas Southwestern Medical Center, Dallas, TX, USA; Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, TX, USA.
authors.forename: Beverly A
authors.initials: BA
authors.lastname: Rothermel
authors.affiliation: Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Per
authors.initials: P
authors.lastname: Uhlén
authors.affiliation: Department of Internal Medicine, Cardiology Division, University of Texas Southwestern Medical Center, Dallas, TX, USA; Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, TX, USA.
authors.forename: Joseph A
authors.initials: JA
authors.lastname: Hill
authors.affiliation: Centro de Estudios Moleculares de la Célula, Facultad de Ciencias Químicas y Farmacéuticas & Facultad de Medicina, Universidad de Chile, Santiago, Chile; Department of Internal Medicine, Cardiology Division, University of Texas Southwestern Medical Center, Dallas, TX, USA; Advanced Center for Chronic Diseases, Facultad de Ciencias Químicas y Farmacéuticas & Facultad de Medicina, Universidad de Chile, Santiago, Chile. Electronic address: slavander@uchile.cl.
authors.forename: Sergio
authors.initials: S
authors.lastname: Lavandero
mesh_terms: D000818:Animals; D015220:Calcium Channels / Q000378:metabolism; D020013:Calcium Signaling; D002467:Cell Nucleus / Q000378:metabolism*; D003600:Cytosol / Q000378:metabolism; D006801:Humans; D008954:Models, Biological; D032383:Myocytes, Cardiac / Q000378:metabolism*
chemical_list: D015220:Calcium Channels
keywords: Angiotensin II; Cardiomyocyte; Endothelin-1; Insulin-like growth factor-1; Nuclear Ca(2+); Sarcolemmal receptor