# The role of Cornichon Homologue proteins in cytosolic calcium homeostasis through sorting and activity  of plant ionotropic- Glutamate Receptor-Like channels

> **NIH NIH R01** · UNIV OF MARYLAND, COLLEGE PARK · 2020 · $339,900

## Abstract

Project Summary
Calcium signaling is fundamental in all eukaryotic cells. Its existence relies on the homeostatic maintenance
of sub-micromolar levels of cytosolic calcium ([Ca2+]cyt). Abnormal perturbation of this basal level triggers a
number of pathologies, from cancer to neurodegeneration and apoptosis. This proposal will focus on the
provocative hypothesis that vesicular traffic and protein targeting by plant CORNICHON-homologue (CNIH)
proteins have a direct regulatory role in [Ca2+]cyt homeostasis and signalling. My group was pioneer in
showing that GLUTAMATE RECEPTOR-like (GLR) proteins are Ca2+ permeable ion channels in plants.
CORNICHON proteins are ER cargo adaptors mediating the recruitment of integral membrane proteins into
COPII vesicles. Here we present evidence that pairs of CNIHs are a necessary condition for the selective
targeting of GLRs to specific endomembrane compartments, resulting in their differential localization to
different Ca2+ stores. These results made us hypothesize that CNIHs themselves have a feed-back role in
Ca2+ homeostasis by controlling the quantity and types of channels that are targeted to these stores. This
hypothesis was further substantiated by our finding that the interaction between GLRs and CNIHs gate
substantial ion currents in the absence of a ligand. We will test this hypothesis by a combination of
genetics, quantitative Ca2+ imaging, mathematical modelling, electrophysiology and protein structural
analysis, focusing on three specific aims. (1) We will manipulate CNIH action by over-expression, by
changing molecular determinants of cargo sorting and domain swaps within the 5 CNIHs expressed in
Arabidopsis. This will allow us to re-address or retain specific GLRs to different subcellular locations. We
predict this will produce growth phenotypes by crossing [Ca2+]cyt homeostasis boundaries, which will inform
us of the functional hierarchy of the trafficking mechanisms affected. (2) We will develop mathematical
models to simulate the relevance of each sub-cellular location to [Ca2+]cyt. We will calibrate these models by
screening a vast array of multiple, combined mutations in the GLR/CNIH families, and quantify their Ca2+
choreography changes and GLR localization. This approach will result in phenotypes that will reveal
hierarchical contributions of each GLR/location set. Finally (3) we will study the physical interaction of
CNIHs and GLRs by electrophysiology after heterologous expression in mammalian cells and by Cryo-EM.
Results should enable us to establish a novel model of [Ca2+]cyt regulation based on vesicular trafficking
mediated by CNIHs. We argue that this mechanism may be more visible and relevant in plants because
they lack all the molecular machinery that animal cells evolved for coordinating small ligand operated Ca2+
stores (such as IP3 and ryanodine receptors, cyclases and phosphodiesterases). However, similar
functional interactions between these two classes of proteins exist in yea...

## Key facts

- **NIH application ID:** 10003363
- **Project number:** 5R01GM131043-02
- **Recipient organization:** UNIV OF MARYLAND, COLLEGE PARK
- **Principal Investigator:** Jose A Feijo
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $339,900
- **Award type:** 5
- **Project period:** 2019-09-01 → 2023-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10003363

## Citation

> US National Institutes of Health, RePORTER application 10003363, The role of Cornichon Homologue proteins in cytosolic calcium homeostasis through sorting and activity  of plant ionotropic- Glutamate Receptor-Like channels (5R01GM131043-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10003363. Licensed CC0.

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