Angiotensin II mediates the axonal trafficking of tyrosine hydroxylase and dopamine β‐hydroxylase mRNAs and enhances norepinephrine synthesis in primary sympathetic neurons

Abstract

In the sympatho‐adrenal system, angiotensin II (Ang II) acts as a key neuromodulatory component. At sympathetic nerve terminals, Ang II influences sympathetic transmission by enhancing norepinephrine (NE) synthesis, facilitating NE release and inhibiting NE uptake. Previously, it was demonstrated that tyrosine hydroxylase (TH) mRNA is trafficked to the distal axons of primary superior cervical ganglia (SCG) neurons, directed by a cis‐acting regulatory element (i.e. zipcode) located in the 3'UTR of the transcript. Results of metabolic labeling studies established that the mRNA is locally translated. It was further shown that the axonal trafficking of the mRNA encoding the enzyme plays an important role in mediating dopamine (DA) and NE synthesis and may facilitate the maintenance of axonal catecholamine levels. In the present study, the hypothesis was tested that Ang II induces NE synthesis in rat primary SCG neurons via the modulation of the trafficking of the mRNAs encoding the catecholamine synthesizing enzymes TH and dopamine β‐hydroxylase (DBH). Treatment of SCG neurons with the Ang II receptor type 1 (AT1R) agonist, L‐162,313, increases the axonal levels of TH and DBH mRNA and protein and results in elevated NE levels. Conversely, treatment of rat SCG neurons with the AT1R antagonist, Eprosartan, abolished the L‐162,313‐mediated increase in axonal levels of TH and DBH mRNA and protein. In a first attempt to identify the proteins involved in the Ang II‐mediated axonal transport of TH mRNA, we used a biotinylated 50‐nucleotide TH RNA zipcode as bait in the affinity purification of TH zipcode‐associated proteins. Mass spectrometric analysis of the TH zipcode ribonucleoprotein (RNP) complex immune‐purified from SCG neurons led to the identification of 163 somal and 127 axonal proteins functionally involved in binding nucleic acids, the translational machinery or acting as subunits of cytoskeletal and motor proteins. Surprisingly, immune‐purification of the TH axonal trafficking complex, results in the acquisition of DBH mRNA, suggesting that these mRNAs maybe transported to the axon together, possibly in the same RNP complex. Taken together, our results point to a novel mechanism by which Ang II participates in the regulation of axonal synthesis of NE by modulating the local trafficking and expression of TH and DBH, two key enzymes involved in the catecholamine biosynthetic pathway.

ACE2 expression in rat brain: Implications for COVID-19 associated neurological manifestations

“…The infusion of angiotensin II in striatum provoke local dopamine release (Brown, Steward et al 1996). Angiotensin II has been shown to regulate the synthesis of the enzymes involved in catecholamine biosynthesis (Aschrafi, Berndt et al 2019). Moreover, ACE2 has been reported in the mitochondria isolated form cell cultures derived from dopaminergic neurons (Costa-Besada, Valenzuela et al 2018).…”

The intracellular renin-angiotensin system: Friend or foe. Some light from the dopaminergic neurons

“…In the brain, Ang II-dopamine interaction was initially suggested by microdialysis studies, which observed that acute striatal perfusion of Ang II led to striatal dopamine release that was inhibited by AT1 antagonists ( Brown et al, 1996 ; Mendelsohn et al, 1993 ). More recently, Ang II was observed to regulate the axonal synthesis of norepinephrine and dopamine by modulating trafficking and expression of tyrosine hydroxylase and dopamine β-hydroxylase, two key enzymes for catecholamine biosynthesis ( Aschrafi et al, 2019 ). We have shown counterregulation between dopamine and angiotensin receptors in the nigrostriatal system ( Villar-Cheda et al, 2014 , 2010 ), and dimerization between AT1 and D2 receptors in striatal neurons ( Martinez-Pinilla et al, 2015 ).…”

SARS-CoV-2 Dissemination Through Peripheral Nerves Explains Multiple Organ Injury

“…For their replication and neuronal dissemination, neuroinvasive viruses must express proteins that control vesicular traffic ( Enquist, 2012 ). Angiotensin II increases and mediates neuronal vesicular trafficking ( Wang et al, 2001 ; Aschrafi et al, 2019 ), and since the receptor binding site of S-glycoproteins in SARS-CoV-2 is structurally similar to angiotensin II, the virus might be capable of increasing and modulating the neuronal vesicular trafficking system in the same manner (see Figure 1B ). Moreover, as coronaviruses modify and assembly inside of structures derived from endoplasmic reticulum, we further suggest that SARS-CoV-2 could also utilize continuous longitudinally spanning endoplasmic reticula, which were described in the myelinated axons, and which are likely a continuation of the somatic organelles ( Gonzalez and Couve, 2014 ).…”