Tyrosiinihydroksylaasigeeni

1.  ( on mahdollista nostaa biopteriinin pitoisuutta supplementtina:Tämä  artikkeli sinänsä koskee malariatutkimuksia.  Tietysti foolihapon käyttö tukee biopteriinin  metaboliaa ihmisellä. Tässä on hiirikoetuloksia,  miten biopteriinin saa myös kudoksissa nousemaan. Dopamiinisynteesi vaatii biopteriinin muodostusta kehossa.   "The continuous infusion of sepiapterin (a BH4 precursor) and citrulline (an arginine precursor) raised the concentrations of BH4 and arginine in both blood and tissue compartments. The restoration of systemic BH4 and arginine availability in infected mice produced only a minor improvement in whole blood nitrite concentrations, a biomarker of NO synthesis, and failed to prevent the onset of severe disease symptoms. However, sepiapterin and citrulline infusion reduced the ratio of phenylalanine to tyrosine in plasma, aortic tissue, and brain tissue. In summary, BH4 depletion in P. berghei infection may compromise both nitric oxide synthesis and phenylalanine metabolism; however, these findings require further investigation in human patients with severe malaria.")
2.  
3.  https://www.ncbi.nlm.nih.gov/pubmed/27641435
4.  TH  (11p15.5)

   Also known as

   TYH; DYT14; DYT5b

   Summary

   The protein encoded by this gene is involved in the conversion of tyrosine to dopamine. It is the rate-limiting enzyme in the synthesis of catecholamines, hence plays a key role in the physiology of adrenergic neurons. Mutations in this gene have been associated with autosomal recessive Segawa syndrome. Alternatively spliced transcript variants encoding different isoforms have been noted for this gene. [provided by RefSeq, Jul 2008]

   Expression

   Restricted expression toward adrenal (RPKM 42.8) See more

   Preferred Names

   tyrosine 3-monooxygenase

   Names

   dystonia 14

   tyrosine 3-hydroxylase

   NM_000360.4 → NP_000351.2  tyrosine 3-monooxygenase isoform b
   See identical proteins and their annotated locations for NP_000351.2
   
   Status: REVIEWED

   Description

   Transcript Variant: This variant (2) uses a different donor splice site at the first coding exon and is missing an adjacent in-frame coding exon compared to transcript variant 1, resulting in an isoform (b) missing a 31 aa segment compared to isoform a.

   Source sequence(s)

   Conserved Domains (4) summary

   TIGR01269
   Location:38 → 494

   Tyr_3_monoox; tyrosine 3-monooxygenase, tetrameric

   cd04930
   Location:38 → 159

   ACT_TH; ACT domain of the nonheme iron-dependent aromatic amino acid hydroxylase, tyrosine hydroxylases (TH)

   pfam00351
   Location:164 → 494

   Biopterin_H; Biopterin-dependent aromatic amino acid hydroxylase

   pfam12549
   Location:2 → 26

   TOH_N; Tyrosine hydroxylase N terminal

Retina ja sumoylaatio

https://nebraska.pure.elsevier.com/en/publications/sumoylation-regulation-of-retina-development-and-functions
 Zhang, L., & Li, D. W. C. (2016). SUMOylation regulation of retina development and functions. Current Molecular Medicine, 16(9), 803-808. https://doi.org/10.2174/1566524016666161128115453

The structure and developmental mechanisms of vertebrate retina are highly conserved. One of the most distinctive events during retinogenesis is the temporally and spatially generation of seven types of retinal cells from the multipotent retinal progenitor cells. The importance and prevalence of SUMOylation in regulation of this process through modulation of gene expression and protein function diversity have been increasingly appreciated.
Here, we review the biological significance of SUMOylation in retina development, examine how SUMOylation balances the proliferation and cell cycle exit of retinal progenitor cells, and finally discuss the molecular mechanisms mediating the specification of different retina neurons and photoreceptors through modulation of various transcription factors
The potential role of SUMOylation in normal retina function is illustrated by the abundant expression of key components of SUMOylation machinery in mouse retina, and is also exemplified by the highly conserved SUMOylation site on neurotransmission receptors in ganglion cells.

KAR ja GlyR , SENP1 ja PKC-sumoylaatiosta riippuva säätelytie tärkeä neuronin ärtyvyydelle

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4199113/

Nat Commun. 2014 Sep 19; 5: 4980.

Published online 2014 Sep 19. doi: 10.1038/ncomms5980

PMCID: PMC4199113

PMID: 25236484

Kainate receptor activation induces glycine receptor endocytosis through PKC deSUMOylation

Hao Sun,^1,* Li Lu,^1,* Yong Zuo,^1,* Yan Wang,¹ Yingfu Jiao,¹ Wei-Zheng Zeng,¹ Chao Huang,² Michael X. Zhu,³ Gerald W. Zamponi,⁴ Tong Zhou,⁵ Tian-Le Xu,¹ Jinke Cheng,¹ and Yong Li^a,1

 Abstract

Surface expression and regulated endocytosis of glycine receptors (GlyRs) play a critical function in balancing neuronal excitability. 

SUMOylation (SUMO modification) is of critical importance for maintaining neuronal function in the central nervous system. 

Here we show that activation of kainate receptors (KARs) causes GlyR endocytosis in a calcium- and protein kinase C (PKC)-dependent manner, leading to reduced GlyR-mediated synaptic activity in cultured spinal cord neurons and the superficial dorsal horn of rat spinal cord slices. 

This effect requires SUMO1/sentrin-specific peptidase 1 (SENP1)-mediated deSUMOylation of PKC, indicating that the crosstalk between KARs and GlyRs relies on the SUMOylation status of PKC. SENP1-mediated deSUMOylation of PKC is involved in the kainate-induced GlyR endocytosis and thus plays an important role in the anti-homeostatic regulation between excitatory and inhibitory ligand-gated ion channels.

 Altogether, we have identified a SUMOylation-dependent regulatory pathway for GlyR endocytosis, which may have important physiological implications for proper neuronal excitability.


Taken together, these findings support the mechanism by which SENP1 regulates kainate-induced GlyR endocytosis via changing the SUMOylation status and activity of PKC.

Neuronin sumoylaatio ja desumoylaatiotasapaino on tärkeä neuronin funktiolle

https://www.ncbi.nlm.nih.gov/pubmed/309049

Sumoylaatio on  palautuva (reversible)   posttranslationaalinen modifikaatio (PTM), joka on välttämätön  neuronaalisen funktion modulaatiossa, johon kuuluu hermonvälittäjäaineiden vapautuminen ja synaptinen muovautuvuus. Tiukasti säätynyt tasapaino sumoylaatio- ja desumoylaatioprosessien kesken on kriittinen aivojen toiminnalle ja tasapainon rikkoutumaa on assosioitu useisiin neurologisiin häiriöihin.Tätä sumoylaatio/desumoylaatiotasapainoa  hallinnoi yksittäinen SUMO:a konjugoiva  entsyymi Ubc9 ja joukko deSUMOylaaseja joita sanotaan sentriinispesifisiksi proteaaseiksi, SENP.
Aiemmin työryhmä jo osoitti, että tyypin 5 metabolisten Glu-reseptorien  aktivaatio liipaisee esiin ohimenevän Ubc9- esiintymän  dendriittihaarakkeissa, mikä johtaa nopeaan  nousuun synaptisessa SUMOyloitumisessa. Kuitenkaan ei vielä oltu  selvitetty   lisääntynyttä  synaptista sumoylaatiota tasapainottavaa mekanismia, joten tutkijaryhmä  alkoi  selvittää SENP1- entsyymin diffuusio.ominaisuuksia käyttämällä  kombinoituja biokemiallisia  lähestymistapoja  ja  yksittäisten hippokampihaarakkeiden valovaikutukseen perustuvia  menetelmiä (photobleaching/ photoconversion). He osoittivat, että mGlu5R-aktivaatio johti ajasta riippuvaan  laskuun SENP1:n poistumistahdissa  yksittäisestä  hippokampihaarakkeesta. Aiheutunut SENP1:n postsynaptinen kertymä  palautti alkuperäistasoihin synaptisen sumoylaation. Kaiken kaikkiaan tutkijoiden löydöt  paljastivat, että mGluR-järjestelmä on sentraalinen aktiviteetista riippuva mekanismi, joka pitää yllä sumoylaation homeostaasia imettäväissynapsissa.

Cell Mol Life Sci. 2019 Mar 23. doi: 10.1007/s00018-019-03075-8. [Epub ahead of print]

The synaptic balance between sumoylation and desumoylation is maintained by the activation of metabotropic mGlu5 receptors.

Schorova L¹, Pronot M¹, Poupon G¹, Prieto M¹, Folci A¹, Khayachi A¹, Brau F¹, Cassé F¹, Gwizdek C¹, Martin S². Abstract

Sumoylation is a reversible post-translational modification essential to the modulation of neuronal function, including neurotransmitter release and synaptic plasticity. A tightly regulated equilibrium between the sumoylation and desumoylation processes is critical to the brain function and its disruption has been associated with several neurological disorders. This sumoylation/desumoylation balance is governed by the activity of the sole SUMO-conjugating enzyme Ubc9 and a group of desumoylases called SENPs, respectively. We previously demonstrated that the activation of type 5 metabotropic glutamate receptors (mGlu5R) triggers the transient trapping of Ubc9 in dendritic spines, leading to a rapid increase in the overall synaptic sumoylation. However, the mechanisms balancing this increased synaptic sumoylation are still not known. Here, we examined the diffusion properties of the SENP1 enzyme using a combination of advanced biochemical approaches and restricted photobleaching/photoconversion of individual hippocampal spines. We demonstrated that the activation of mGlu5R leads to a time-dependent decrease in the exit rate of SENP1 from dendritic spines. The resulting post-synaptic accumulation of SENP1 restores synaptic sumoylation to initial levels. Altogether, our findings reveal the mGlu5R system as a central activity-dependent mechanism to maintaining the homeostasis of sumoylation at the mammalian synapse. KEYWORDS: Desumoylation; SENP1; Sumoylation; Synapse; mGlu5 receptor