The synthesis and release of catecholamines epinephrine, norepinephrine and dopamine are triggered by various but distinct conditions and stresses. Dopamine (DA) acts a neurotransmitter and neuromodulator in the brain and peripherally, as an autocrine/paracrine hormone. Dopamine exerts its major role in the nervous system where is involved in motor control and action selection, reward and motivation, behavior, memory and cognition. The five G protein-coupled (GPCR) DA receptors are subdivided in
to two subtypes: D1-like type with dopamine receptors 1 (DRD1) and 5 (DRD5) and D2-like type with dopamine receptors 2 (DRD2), 3 (DRD3) and 4 (DRD4). They differ in expression and ligand affinity, and the alpha subunits of heterotrimeric G proteins to which they couple. Dopaminergic (DA-producing) neurons are primarily in modbrain areas such as the substantia nigra pars compacta (SNc) and the ventral tegmental areas (VTA). The precursor of all catecholamines is L-tyrosine which can be derived from the diet or from the hydroxylation of L-phenylalanine. Tyrosine hydroxylase (Th), an iron-containing, biopterin-dependent soluble enzyme catalyzes the conversion of tyrosine to dihydroxy-L-phenylalanine (L-DOPA) in the rate-limiting step of the reaction. The cofactor tetrahydrobioterin (BH4) is used in the reaction and the resulting dihydrobiopterin (BH2) is reconverted to BH4 by dihydropteridine reductase. Tetrahydrobiopterin can also be synthesized de novo from the purine nucleotide GTP. Th expression and activity is regulated in manifold ways. The short term control of Th activity is due to product(s)-based inhibitory feedback and activation by phosphorylation; several kinases and phosphatases have been implicated in modulating the activity of the enzyme. Long term control involves regulation of transcription and epigenetic mechanisms, stability and in humans, alternative splicing giving rise to four different isoforms. Th exists as a tetramer. Each monomer consists of a regulatory N-terminal stretch followed by the catalytic and tetramerization domains. Access the structure of the catalytic domain; or the structures of both catalytic and tetramerization domains. L-DOPA is converted to dopamine (DA) by the pyridoxal phosphate-dependent aromatic L-amino acid decarboxylase (Ddc). Both Th and Ddc interact with vesicle protein Slc18a2, which couples DA synthesis with transport into vesicles. Cytosolic DA is prone to oxidation to generate toxic quinones; the low pH inside the vesicle protects DA from oxidation. DA can be converted to norepinephrine which in turn, can be methylated to yield epinephrine. SNc DA neurons are selectively lost in the neurodegenerative Parkinson disease (PD). Interestingly, Th is an interacting partner for alpha-synuclein, a major culprit in PD. To see the ontology report for annotations GViewer and download, click here...(less)
