Gp130 cytokines stimulate proteasomal degradation of tyrosine hydroxylase in sympathetic neurons by ERK‐dependent pathway

Abstract

Heterogeneity of sympathetic transmission in the heart after myocardial infarction contributes to ventricular arrhythmias and sudden cardiac death. Tyrosine hydroxylase (TH), the rate‐limiting enzyme in norepinephrine synthesis, is depleted in the left ventricle after myocardial infarction, but elevated in other parts of heart. Inflammatory cytokines acting through gp130 cause local depletion of TH in cardiac sympathetic nerves post infarction. However, the mechanism of cytokine‐induced TH loss remains unknown. We used cultured sympathetic neurons to investigate the mechanism of gp130 cytokine suppression of TH protein. Cytokines stimulate TH ubiquitination, and cytokine‐induced TH loss was prevented by MG‐132, suggesting that the proteasomal degradation pathway was involved. Cytokine activation of gp130 stimulates Janus kinase (JAK) which leads to activation of STAT3, ERK1/2, and PI3K/AKT. Blocking ERK activation by U0126 prevented cytokine‐induced TH ubiquitination, while inhibiting STAT3 phosphorylation with STAT3 inhibitor V enhanced cytokine‐induced TH ubiquitination. Inhibiting STAT3 enhanced ERK1/2 phosphorylation, suggesting that ERK was a major regulator of TH ubiquitination. Blocking JAK activity inhibited all downstream signaling and prevented cytokine‐induced ubiquitination of TH. Preliminary data implicate SOCS3 as a mediator of ERK‐STAT3 crosstalk.