# Supplement:  Metalloendocrinology: Mapping Bioinorganic Chemistry in the Extracellular Space

> **NIH NIH R35** · UNIVERSITY OF CALIFORNIA AT DAVIS · 2023 · $60,911

## Abstract

PROJECT ABSTRACT
Copper is an essential micronutrient in biology, playing fundamental roles in processes such as respiration and
antioxidant defense. The context in which a copper ion resides is vital to its activity, and its
miscompartmentalization and imbalances is associated with a host of disorders. While technologies have
emerged to investigate intracellular copper dynamics, the extracellular copper pool is relatively under-
characterized. The parent grant of this supplement seeks to elucidate the speciation of metals in the extracellular
space, with a focus on the interplay of metals with another dynamic component in the extracellular environment,
hormones. The main research of this objective focuses on a particular peptide with hormone-like functions, C-
peptide, a 31-mer derived from the proinsulin protein. Historically undervalued as an innocent secondary marker
for insulin, C-peptide is of increasing interest for its bioactivity independent of insulin. However, its advancement
has been hampred by lack of mechanistic understanding. Work under the parent project has shown that C-
peptide can directly bind to copper, an event that can modulate C-peptide's activity. In Aim 1 of this proposal, we
seek to determine whether and how C-peptide and its truncates affect copper trafficking. Preliminary work
suggests that the metal-binding interaction can shift the homeostatic balance of the metal. A combination of in
vitro and in vivo work will seek to analyze the pathways that drive the interplay between C-peptide and copper.
Aim 2 seeks to leverage the interactions of copper and C-peptide to identify a plasma membrane receptor for
the peptide. While an orphan GPCR, GPR146, has been proposed as a partner for C-peptide, this claim remains
debated. We hypothesize that metal interactions with the peptide, which is rich in negatively-charged residues,
may be influential in receptor recognition. This aim will screen for C-peptide interactions with a library of orphan
GPCRs in the presence and absence of transition metals to determine whether metals are integral to receptor
recognition, and if so, identify a cognate receptor for the peptide. To achieve these research goals, the candidate
to be supported by this supplement will be trained across disciplines with a multifaceted mentoring team to bring
molecular insight to metalloendocrinological processes.

## Key facts

- **NIH application ID:** 10689412
- **Project number:** 3R35GM133684-04S1
- **Recipient organization:** UNIVERSITY OF CALIFORNIA AT DAVIS
- **Principal Investigator:** Marie C. Heffern
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $60,911
- **Award type:** 3
- **Project period:** 2019-09-01 → 2024-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10689412

## Citation

> US National Institutes of Health, RePORTER application 10689412, Supplement:  Metalloendocrinology: Mapping Bioinorganic Chemistry in the Extracellular Space (3R35GM133684-04S1). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/10689412. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*