Tyrosine hydroxylase conditional KO mice reveal peripheral tissue-dependent differences in dopamine biosynthetic pathways

Katsuya Miyajima,Chiaki Kawamoto,Satoshi Hara,Masayo Mori-Kojima,Tamae Ohye,Chiho Sumi-Ichinose,Nae Saito,Toshikuni Sasaoka,Daniel Metzger,Hiroshi Ichinose

doi:10.1016/j.jbc.2021.100544

Abstract

Dopamine (DA) exerts well-known functions in the brain as a neurotransmitter. In addition, it plays important physiological roles in peripheral organs, but it is largely unknown how and where peripheral DA is synthesized and regulated. Catecholamines in peripheral tissues are either produced within the tissue itself and/or derived from sympathetic neurons, which release neurotransmitters for uptake by peripheral tissues. To evaluate DA-producing ability of each peripheral tissue, we generated conditional KO mice (cKO mice) in which the tyrosine hydroxylase (TH) gene is ablated in the sympathoadrenal system, thus eliminating sympathetic neurons as a DA source. We then examined the alterations in the noradrenaline (NA), DA, and 3,4-dihydroxyphenylalanine (DOPA) contents in peripheral organs and performed immunohistochemical analyses of TH-expressing cells. In the heart and pancreas of cKO mice, both the TH protein and NA levels were significantly decreased, and the DA contents were decreased in parallel with NA contents, indicating that the DA supply originated from sympathetic neurons. We found TH-immunoreactive cells in the stomach and lung, where the TH protein showed a decreasing trend, but the DA levels were not decreased in cKO mice. Moreover, we found a significant correlation between the DA content in the kidney and the plasma DOPA concentration, suggesting that the kidney takes up DOPA from blood to make DA. The aforementioned data unravel differences in the DA biosynthetic pathway among tissues and support the role of sympathetic neurons as a DA supplier.

Highlights

We further examined the alteration in the Tyrosine hydroxylase (TH) protein in the sympathetic neurons of the heart (Fig. 2B)
We examined alterations in TH expression and quantified the concentrations of DOPA, DA, and NA in the heart, pancreas, stomach, lung, spleen, and kidney of mice in which the Th gene was selectively ablated in the sympathoadrenal system
Plasma DOPA levels were not reduced at either 2 or 4 weeks after TAM injection, the TH protein levels were greatly decreased in the sympathoadrenal system (Fig. 4A)

Summary

Introduction

We presumed that sympathetic neurons release DOPA into the circulation, the plasma DOPA levels of cKO mice were comparable to those of Ctrl mice at both 2 and 4 weeks after TAM injection (Fig. 4A). The TH protein levels in heart and pancreas of cKO mice were significantly decreased to approximately 20% compared with Ctrl mice at both 2 and 4 weeks after TAM injection (Fig. 5, A and B).

Results

Conclusion