Preprint Article Version 1 Preserved in Portico This version is not peer-reviewed

Doxycycline and Minocycline act as Positive Allosteric Modulators of the PAC1 Receptor and Induce Plasminogen Activators in RT4 Schwann Cells

Version 1 : Received: 27 July 2021 / Approved: 27 July 2021 / Online: 27 July 2021 (21:51:30 CEST)

A peer-reviewed article of this Preprint also exists.

Thomas Broome, S.; Musumeci, G.; Castorina, A. Doxycycline and Minocycline Act as Positive Allosteric Modulators of the PAC1 Receptor and Induce Plasminogen Activators in RT4 Schwann Cells. Appl. Sci. 2021, 11, 7673. Thomas Broome, S.; Musumeci, G.; Castorina, A. Doxycycline and Minocycline Act as Positive Allosteric Modulators of the PAC1 Receptor and Induce Plasminogen Activators in RT4 Schwann Cells. Appl. Sci. 2021, 11, 7673.

Journal reference: Appl. Sci. 2021, 11, 7673
DOI: 10.3390/app11167673

Abstract

Regeneration of peripheral nerves depends on the ability of axons to navigate through an altered extracellular environment. It has been suggested that Schwann cells facilitate this process through their secretion of neuropeptides and proteases. Using the RT4-D6P2T Schwann cell line (RT4), we have previously shown that RT4 cultures endogenously express the neuropeptide PACAP, and respond to exogenous stimulation by inducing the expression of tissue plasminogen activator (tPA) and urokinase plasminogen activator (uPA) through PAC1 receptor activation. In this study, based on recent findings showing that doxycycline and minocycline act as positive allosteric modulators (PAMs) of the PAC1 receptor, we tested if treatment with these tetracyclines could induce the expression and activity of tPA and uPA in RT4 cells. Using ELISA and zymographic analyses, we demonstrate that doxycycline and minocycline reliably induce the secretion and activity of both tPA and uPA, which is paralleled by an increased expression levels, as shown by immunocytochemistry and Western blots. These actions were mediated, at least in part, by the PAC1 receptor, as PACAP6-38 mitigated tetracycline-induced expression and activity of tPA and uPA. We conclude that doxycycline and minocycline can act as PAMs of the PAC1 receptor to promote proteolytic activity in RT4 cells.

Keywords

pituitary adenylate cyclase-activating peptide (PACAP); PAC1 receptor; doxycycline; minocycline; positive allosteric modulator; Schwann cells; tissue plasminogen activator (tPA); urokinase plasminogen activator (uPA)

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