# Elementary Events of Intracellular Calcium Signaling

> **NIH NIH R37** · UNIVERSITY OF CALIFORNIA-IRVINE · 2020 · $566,054

## Abstract

Ca2+ ions serve as a signaling mechanism in almost all cell types to regulate numerous diverse functions.
Ca2+ signals are ordered in a hierarchy, from openings of single Ca2+ channels ('fundamental' events),
through the concerted openings of clustered channels ('elementary' events, such as Ca2+ puffs) to
propagating Ca2+ waves, coordinated through Ca2+ diffusion and Ca2+-induced Ca2+ release.
Fundamental and elementary events thus form the triggers and building blocks underlying the complex
spatiotemporal Ca2+ signals that permit graded and selective regulation of cell functions. Our overall goals
are to elucidate how the functional properties, spatial organization and interactions between Ca2-t- channels
pattern spatiotemporal cellular signals. We focus on Ca2+ events underlying the inositol trisphosphate (IP3)
signaling pathway, and Ca2+ flux through amyloid oligomer pores implicated in the pathophysiology of
Alzheimer's disease. Capitalizing on recent advances in biophotonic technology, including total intemal
reflection fluorescence and superresolution microscopy, we can now study these topics at the truly single-
molecule level in intact cells. Our aims are to: (i) Further develop techniques for fast, 3-dimensional imaging
Ca2+ flux through individual IPS receptor/channels (IP3Rs) in intact cells; for monitoring ER [Ca2+]; and for
single-molecule localization of subtypes of native IP3Rs in transgenic mouse models, (ii) Elucidate the
functional properties of IP3Rs in the intact cell, how the activity of channels is orchestrated to generate and
temiinate elementary Ca2+ puffs, and to generate global Ca2+ waves, (iii) Resolve IP3R molecules with
sub-micron precision to address hypotheses concerning the clustered organization and anchoring of these
channels; their interactions via Ca2+ diffusion and allosteric mechanisms; and the putative function of 'silenf
 IP3Rs between puff sites, (iv) Investigate the molecular mechanisms by which amyloid oligomers form Ca2+-
permeable pores by combining single-channel Ca2+ imaging with single-molecule photobleaching of
fluorescent monomers to detennine pore stoichiometry; and elucidate the mechanisms by which intracellular
oligomers induce Ca2+ liberation through IP3Rs.
 RELEVANCE (See instructions):
 Calcium sen/es a 'life or death' function in virtually all cells ofthe body, regulating processes as diverse as
 the heartbeat and synaptic transmission between brain cells, and is implicated in Alzheimer's and other
 diseases. Our goal is to elucidate the hierarchical mechanisms by which calcium signals are generated at
 the single-molecule level, with the dual aims of better understanding their normal functioning and how
disruntions in r-alrJum signaling mav lead to disease.

## Key facts

- **NIH application ID:** 9996745
- **Project number:** 5R37GM048071-29
- **Recipient organization:** UNIVERSITY OF CALIFORNIA-IRVINE
- **Principal Investigator:** IAN PARKER
- **Activity code:** R37 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $566,054
- **Award type:** 5
- **Project period:** 1992-08-01 → 2022-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9996745

## Citation

> US National Institutes of Health, RePORTER application 9996745, Elementary Events of Intracellular Calcium Signaling (5R37GM048071-29). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9996745. Licensed CC0.

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