Local Control of Nuclear Calcium Signaling in Cardiac Myocytes by Perinuclear Microdomains of Sarcolemmal Insulin-Like Growth Factor 1 Receptors

Abstract

Artículo de publicación ISIRationale: The ability of a cell to independently regulate nuclear and cytosolic Ca2+ signaling is currently attributed to the differential distribution of inositol 1,4,5-trisphosphate receptor channel isoforms in the nucleoplasmic versus the endoplasmic reticulum. In cardiac myocytes, T-tubules confer the necessary compartmentation of Ca2+ signals, which allows sarcomere contraction in response to plasma membrane depolarization, but whether there is a similar structure tunneling extracellular stimulation to control nuclear Ca2+ signals locally has not been explored. Objective: To study the role of perinuclear sarcolemma in selective nuclear Ca2+ signaling. Methods and Results: We report here that insulin-like growth factor 1 triggers a fast and independent nuclear Ca2+ signal in neonatal rat cardiac myocytes, human embryonic cardiac myocytes, and adult rat cardiac myocytes. This fast and localized response is achieved by activation of insulin-like growth factor 1 receptor signaling complexes present in perinuclear invaginations of the plasma membrane. The perinuclear insulin-like growth factor 1 receptor pool connects extracellular stimulation to local activation of nuclear Ca2+ signaling and transcriptional upregulation through the perinuclear hydrolysis of phosphatidylinositol 4,5-biphosphate inositol 1,4,5-trisphosphate production, nuclear Ca2+ release, and activation of the transcription factor myocyte-enhancing factor 2C. Genetically engineered Ca2+ buffers—parvalbumin—with cytosolic or nuclear localization demonstrated that the nuclear Ca2+ handling system is physically and functionally segregated from the cytosolic Ca2+ signaling machinery. Conclusions: These data reveal the existence of an inositol 1,4,5-trisphosphate–dependent nuclear Ca2+ toolkit located in direct apposition to the cell surface, which allows the local control of rapid and independent activation of nuclear Ca2+ signaling in response to an extracellular ligan

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“…Depending on the subcellular location and spatial association of the signaling molecules and their effectors, PDGF may preferentially activate Ca 2ϩ release from the centrally located Ca 2ϩ stores, instead of the membrane Ca 2ϩ -permeating channels. It is consistent with reports that mitogens and growth factors stimulate Ca 2ϩ release from Ca 2ϩ stores in the perinuclear regions and/or nucleoplasmic reticulum to regulate gene transcription and cell proliferation in other cell types (2,9,18,20,41,57 …”

Novel players in cardioprotection: Insulin like growth factor-1, angiotensin-(1–7) and angiotensin-(1–9)

“…Despite that classical IGF-1/Akt/ERK axis signaling has been well established [29,38,39,41], there is evidence regarding the involvement of a non-canonical G protein-mediated pathway in several cell types [59][60][61][62][63], including cardiomyocytes [64][65][66]. In this context, IGF-1 can also activates via the pertussis toxin-sensitive heterotrimeric G protein the phospholipase C (PLC) and, subsequently increases the intracellular levels of inositol-1,4,5-triphosphate (InsP 3 ) which activates InsP3 receptors producing nucleoplasmic [64] and cytoplasmic [65] Ca 2+ increases.…”

“…In this context, IGF-1 can also activates via the pertussis toxin-sensitive heterotrimeric G protein the phospholipase C (PLC) and, subsequently increases the intracellular levels of inositol-1,4,5-triphosphate (InsP 3 ) which activates InsP3 receptors producing nucleoplasmic [64] and cytoplasmic [65] Ca 2+ increases. Moreover, IGF-1-dependent hypertrophy is mediated by Gβγ-subunits/Ca 2+ /PKCα/ERK pathway [66], associated with increased [ 3 H]-leucine uptake in cultured rat cardiomyocytes [67].…”

Novel Therapeutic Targets in Heart Failure: The Phospholipase Cβ1b–Shank3 Interface

“…52 There have been suggestions of a role for PLC in cardiomyocyte responses to IGF1 (insulin-like growth factor-1), 53 and this would most likely be PLCγ, although this was not verified. In our hands, overexpression of PLCγ1 in cardiomyocytes did not alter responses to either EGF or PDGF.…”