The entry of Ca2+ ions into the cytosol from the extracellular fluid and from endoplasmic reticulum (ER) stores is used as a signaling mechanism by virtually all cell types to regulate functions as diverse as electrical excitability, secretion, proliferation and cell death. Improved optical technology now enables visualization of a hierarchy of Ca2+ signaling events, ranging from openings of single-channel Ca2+-permeable channels ('fundamental'events), concerted openings of clustered channels ('elementary'events) and propagating Ca2+ waves. The localized free [Ca2+] elevations arising through individual and clustered channels serve autonomous signaling functions, and their activity may further be coordinated through Ca2+ diffusion and Ca2+-induced Ca2+ release to propagate global cellular Ca2+ waves: Fundamental and elementary events thus form hierarchical building blocks underlying the complex spatiotemporal Ca2+ signals hat permit graded and selective regulation of cell functions. Elucidation of their generation, interaction and functional consequences is, therefore, pivotal to understand the physiological functioning of the ubiquitous Ca2+ messenger pathway and its involvement in disease. Our overall goals are to elucidate how cells generate the hierarchy of Ca2+ signals, how these are utilized for specific and localized regulation of effector responses, and how disruptions in the signaling pathway may be involved in disease pathogenesis. By utilizing advanced biophotonic tools - including confocal, multi-focal and total internal reflection microscopy, in conjunction with photolysis of caged second messengers and neurotransmitters we aim to: (i) Develop improved optical techniques so as to image Ca2+ flux through individual channels in the plasma membrane and ER of intact cells, (ii) Utilize simultaneous imaging of hundreds of single-channels to explore differences in their gating, and study self- and inter-channel modulation by Ca2+ microdomains. (iii) Elucidate how the activity of individual IP3R at a release site is orchestrated to generate elementary Ca2+ puffs, (iv) Investigate the hierarchy of spatio-temporal patterning of the IPs/Ca2+ messenger pathway in neuronal signaling, and in the pathogenesis of Parkinson's disease. Calcium serves a 'life or death'function in virtually all cells of the body, regulating processes as diverse as the heartbeat and synaptic transmission between brain cells and is implicated in numerous diseases including Alzheimer's and Parkinson's. Our goal is to elucidate the hierarchical mechanisms by which Ca2+ signals are generated at levels from single molecules to the whole cell, with the dual aims of better understanding their normal functioning and how disruptions in Ca2+ signaling, may lead to disease.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Research Project (R01)
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Neurotransporters, Receptors, and Calcium Signaling Study Section (NTRC)
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Shapiro, Bert I
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University of California Irvine
Other Basic Sciences
Schools of Arts and Sciences
United States
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Ellefsen, Kyle L; Parker, Ian (2018) Dynamic Ca2+ imaging with a simplified lattice light-sheet microscope: A sideways view of subcellular Ca2+ puffs. Cell Calcium 71:34-44
Parker, Ian; Evans, Katrina T; Ellefsen, Kyle et al. (2017) Lattice light sheet imaging of membrane nanotubes between human breast cancer cells in culture and in brain metastases. Sci Rep 7:11029
Lock, Jeffrey T; Smith, Ian F; Parker, Ian (2017) Comparison of Ca2+puffs evoked by extracellular agonists and photoreleased IP3. Cell Calcium 63:43-47
Lock, Jeffrey T; Parker, Ian; Smith, Ian F (2016) Communication of Ca(2+) signals via tunneling membrane nanotubes is mediated by transmission of inositol trisphosphate through gap junctions. Cell Calcium 60:266-72
Lock, Jeffrey T; Parker, Ian; Smith, Ian F (2015) A comparison of fluorescent Ca²? indicators for imaging local Ca²? signals in cultured cells. Cell Calcium 58:638-48
Rückl, Martin; Parker, Ian; Marchant, Jonathan S et al. (2015) Modulation of elementary calcium release mediates a transition from puffs to waves in an IP3R cluster model. PLoS Comput Biol 11:e1003965
Schmunk, G; Boubion, B J; Smith, I F et al. (2015) Shared functional defect in IP?R-mediated calcium signaling in diverse monogenic autism syndromes. Transl Psychiatry 5:e643
Demuro, Angelo; Parker, Ian (2015) Picomolar sensitivity to inositol trisphosphate in Xenopus oocytes. Cell Calcium 58:511-7
Lock, Jeffrey T; Ellefsen, Kyle L; Settle, Bret et al. (2015) Imaging local Ca2+ signals in cultured mammalian cells. J Vis Exp :
Matheu, Melanie P; Othy, Shivashankar; Greenberg, Milton L et al. (2015) Imaging regulatory T cell dynamics and CTLA4-mediated suppression of T cell priming. Nat Commun 6:6219

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