Acute Regulation of Tyrosine Hydroxylase by Nerve Activity and by Neurotransmitters via Phosphorylation

Zigmond, Richard E.; Schwarzschild, M. A.; Rittenhouse, Ann R.

doi:10.1146/annurev.ne.12.030189.002215

Cited by 492 publications

(274 citation statements)

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“…TH is the rate‐limiting enzyme of NE production with its activity regulated by phosphorylation at Ser 31 (but not Ser 40 ; Zigmond et al , 1989; Dickson & Briggs, 2013; Tekin et al , 2014). Particularly, CNTF, like physical stressors (Ong et al , 2014), stimulates TH activity through Ser 31 phosphorylation (Shi et al , 2012b).…”

Section: Resultsmentioning

confidence: 99%

Hypothalamic CNTF volume transmission shapes cortical noradrenergic excitability upon acute stress

et al. 2018

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Stress‐induced cortical alertness is maintained by a heightened excitability of noradrenergic neurons innervating, notably, the prefrontal cortex. However, neither the signaling axis linking hypothalamic activation to delayed and lasting noradrenergic excitability nor the molecular cascade gating noradrenaline synthesis is defined. Here, we show that hypothalamic corticotropin‐releasing hormone‐releasing neurons innervate ependymal cells of the 3rd ventricle to induce ciliary neurotrophic factor (CNTF) release for transport through the brain's aqueductal system. CNTF binding to its cognate receptors on norepinephrinergic neurons in the locus coeruleus then initiates sequential phosphorylation of extracellular signal‐regulated kinase 1 and tyrosine hydroxylase with the Ca2+‐sensor secretagogin ensuring activity dependence in both rodent and human brains. Both CNTF and secretagogin ablation occlude stress‐induced cortical norepinephrine synthesis, ensuing neuronal excitation and behavioral stereotypes. Cumulatively, we identify a multimodal pathway that is rate‐limited by CNTF volume transmission and poised to directly convert hypothalamic activation into long‐lasting cortical excitability following acute stress.

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Section: Resultsmentioning

confidence: 99%

Hypothalamic CNTF volume transmission shapes cortical noradrenergic excitability upon acute stress

et al. 2018

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“…At intermediate and caudal levels, the mNTS contains many neurons that express tyrosine hydroxylase (TH), the rate-limiting enzyme in catecholamine biosynthesis (Zigmond et al, 1989). Catecholaminergic neurons in mNTS are sensitive to disturbance of cardiovascular (Chan et al, 1999), respiratory (Buller et al, 1999), fluid (Gordon et al, 1979), and metabolic (Willing and Berthoud, 1997) homeostasis.…”

Section: Introductionmentioning

confidence: 99%

Subcellular localization of nicotinamide adenine dinucleotide phosphate oxidase subunits in neurons and astroglia of the rat medial nucleus tractus solitarius: Relationship with tyrosine hydroxylase immunoreactive neurons

et al. 2006

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Superoxide produced by the enzyme NADPH oxidase mediates crucial intracellular signaling cascades in the mNTS, a brain region populated by catecholaminergic neurons, as well as astroglia that play an important role in autonomic function. The mechanisms mediating NADPH oxidase (phox) activity in the neural regulation of cardiovascular processes are incompletely understood, however the subcellular localization of superoxide produced by the enzyme is likely to be an important regulatory factor. We used immunogold electron microscopy to determine the phenotypic and subcellular localization of the NADPH oxidase subunits p47 phox , gp91 phox, and p22 phox in the mNTS. The mNTS contains a large population of neurons that synthesize catecholamines. Significantly, catecholaminergic signaling can be modulated by redox reactions. Therefore, the relationship of NADPH oxidase subunit labeled neurons or glia with respect to catecholaminergic neurons was also determined by dual labeling for the superoxide producing enzyme and tyrosine hydroxylase (TH), the rate-limiting enzyme in catecholamine biosynthesis. In the mNTS, NADPH oxidase subunits were present primarily in somatodendritic processes and astrocytes, some of which also contained TH, or were contacted by TH labeled axons, respectively. Immunogold quantification of NADPH oxidase subunit localization showed that p47 phox and gp91 phox were present on the surface membrane, as well as vesicular organelles characteristic of calcium storing smooth endoplasmic reticula in dendritic and astroglial processes. These results indicate that NADPH oxidase assembly and consequent superoxide formation are likely to occur near the plasmalemma, as well as on vesicular organelles associated with intracellular calcium storage within mNTS neurons and glia. Thus, NADPH oxidase-derived superoxide may participate in intracellular signaling pathways linked to calcium regulation in diverse mNTS cell types. Moreover, NADPH oxidase-derived superoxide in neurons and glia may directly or indirectly modulate catecholaminergic neuron activity in the mNTS.

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“…First, tyrosine hydroxylase (TH) converts tyrosine into DOPA. TH is the rate-limiting enzyme in DA synthesis, and its regulated activity governs the overall rate of formation for DA (17,18). Early studies showed that TH exists in both cytosolic and membrane-bound forms (19 -22).…”

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confidence: 99%

A Biochemical and Functional Protein Complex Involving Dopamine Synthesis and Transport into Synaptic Vesicles

Cartier

Parra

Baust

et al. 2010

Journal of Biological Chemistry

115

103

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Synaptic transmission depends on neurotransmitter pools stored within vesicles that undergo regulated exocytosis. In the brain, the vesicular monoamine transporter-2 (VMAT 2 ) is responsible for the loading of dopamine (DA) and other monoamines into synaptic vesicles. Prior to storage within vesicles, DA synthesis occurs at the synaptic terminal in a two-step enzymatic process. First, the rate-limiting enzyme tyrosine hydroxylase (TH) converts tyrosine to di-OH-phenylalanine. Aromatic amino acid decarboxylase (AADC) then converts di-OH-phenylalanine into DA. Here, we provide evidence that VMAT 2 physically and functionally interacts with the enzymes responsible for DA synthesis. In rat striata, TH and AADC co-immunoprecipitate with VMAT 2 , whereas in PC 12 cells, TH co-immunoprecipitates with the closely related VMAT 1 and with overexpressed VMAT 2 . GST pull-down assays further identified three cytosolic domains of VMAT 2 involved in the interaction with TH and AADC. Furthermore, in vitro binding assays demonstrated that TH directly interacts with VMAT 2 . Additionally, using fractionation and immunoisolation approaches, we demonstrate that TH and AADC associate with VMAT 2 -containing synaptic vesicles from rat brain. These vesicles exhibited specific TH activity. Finally, the coupling between synthesis and transport of DA into vesicles was impaired in the presence of fragments involved in the VMAT 2 /TH/AADC interaction. Taken together, our results indicate that DA synthesis can occur at the synaptic vesicle membrane, where it is physically and functionally coupled to VMAT 2 -mediated transport into vesicles.Monoamines, including dopamine (DA), 3 norepinephrine (NE), and serotonin (5-HT), are neurotransmitters that play major roles in a variety of brain functions, including emotion, reward, cognition, memory, attention, locomotion, and stress control (1-6). In neurons and neuroendocrine cells, monoamines are stored in large dense core vesicles (LDCVs) and small synaptic vesicles (SVs) (7-11) that undergo regulated exocytosis through a complex network of protein-protein interactions (12). Loading of monoamines into LDCVs and SVs of neurons and neuroendocrine cells is mediated by two vesicular monoamine transporter isoforms: VMAT 1 (13) and VMAT 2 (14). These transporters contain 12 putative transmembrane domains with both the N and C termini facing the cytosolic side of the vesicle membrane. VMAT 1 is mostly present in LDCVs of neuroendocrine cells, including chromaffin and PC12 cells, whereas VMAT 2 is primarily expressed by monoaminergic neurons of the central nervous system (15). In midbrain DA neurons, VMAT 2 is sorted to LDCVs and SVs in axon terminals and to LDCVs and tubulo-vesicular structures in the somatodendritic compartment (7)(8)(9)(10)(11)15).It is generally accepted that VMAT 2 transports DA that has been previously synthesized in the cytosolic compartment of the presynaptic terminal (16). DA synthesis requires two enzymatic reactions. First, tyrosine hydroxylase (TH) converts tyrosine into DOP...

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Acute Regulation of Tyrosine Hydroxylase by Nerve Activity and by Neurotransmitters via Phosphorylation

Cited by 492 publications

References 0 publications

Hypothalamic CNTF volume transmission shapes cortical noradrenergic excitability upon acute stress

Hypothalamic CNTF volume transmission shapes cortical noradrenergic excitability upon acute stress

Subcellular localization of nicotinamide adenine dinucleotide phosphate oxidase subunits in neurons and astroglia of the rat medial nucleus tractus solitarius: Relationship with tyrosine hydroxylase immunoreactive neurons

A Biochemical and Functional Protein Complex Involving Dopamine Synthesis and Transport into Synaptic Vesicles

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