Characterization of pepcan-23 as pro-peptide of RVD-hemopressin (pepcan-12) and stability of hemopressins in mice.

Glasmacher, Sandra; Gertsch, Jürg (2021). Characterization of pepcan-23 as pro-peptide of RVD-hemopressin (pepcan-12) and stability of hemopressins in mice. Advances in biological regulation, 80, p. 100808. Elsevier 10.1016/j.jbior.2021.100808

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Hemopressins ((x)-PVNFKLLSH) or peptide endocannabinoids (pepcans) can bind to cannabinoid receptors. RVD-hemopressin (pepcan-12) was shown to act as endogenous allosteric modulator of cannabinoid receptors, with opposite effects on CB1 and CB2, respectively. Moreover, the N-terminally elongated pepcan-23 was detected in different tissues and was postulated to be the pro-peptide of RVD-hemopressin. Currently, data about the pharmacokinetics, tissue distribution and stability of hemopressin-type peptides are lacking. Here we investigated the secondary structure and physiological role of pepcan-23 as precursor of RVD-hemopressin. We assessed the metabolic stability of these peptides, including hemopressin. Using LC-ESI-MS/MS, pepcan-23 was measured in mouse tissues and human whole blood (~50 pmol/mL) and in plasma was the most stable endogenous peptide containing the hemopressin sequence. Using peptide spiked human whole blood, mouse adrenal gland and liver homogenates demonstrate that pepcan-23 acts as endogenous pro-peptide of RVD-hemopressin. Furthermore, administered pepcan-23 converted to RVD-hemopressin in mice. In circular dichroism spectroscopy, pepcan-23 showed a helix-unordered-helix structure and efficiently formed complexes with divalent metal ions, in particular Cu(II) and Ni(II). Hemopressin and RVD-hemopressin were not bioavailable to the brain and showed poor stability in plasma, in agreement with their overall poor biodistribution. Acute hemopressin administration (100 mg/kg) did not modulate endogenous RVD-hemopressin/pepcan-23 levels or influence the endocannabinoid lipidome but increased 1-stearoyl-2-arachidonoyl-sn-glycerol. Overall, we show that pepcan-23 is a biological pro-peptide of RVD-hemopressin and divalent metal ions may regulate this process. Given the lack of metabolic stability of hemopressins, administration of pepcan-23 as pro-peptide may be suitable in pharmacological experiments as it is converted to RVD-hemopressin in vivo.

Item Type:

Journal Article (Original Article)

Division/Institute:

04 Faculty of Medicine > Pre-clinic Human Medicine > Institute of Biochemistry and Molecular Medicine

Graduate School:

Graduate School for Cellular and Biomedical Sciences (GCB)

UniBE Contributor:

Glasmacher, Sandra Patricia and Gertsch, Jürg

Subjects:

500 Science > 570 Life sciences; biology
600 Technology > 610 Medicine & health

ISSN:

2212-4934

Publisher:

Elsevier

Language:

English

Submitter:

Barbara Franziska Järmann-Bangerter

Date Deposited:

02 Dec 2021 09:09

Last Modified:

05 Dec 2021 01:46

Publisher DOI:

10.1016/j.jbior.2021.100808

PubMed ID:

33799079

Uncontrolled Keywords:

Cannabinoid receptors Hemopressin Metal binding Pepcans Peptides

BORIS DOI:

10.48350/161545

URI:

https://boris.unibe.ch/id/eprint/161545

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