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Digital archive of theses discussed at the University of Pisa

 

Thesis etd-12232021-231927


Thesis type
Tesi di specializzazione (4 anni)
Author
CARLI, MARCO
URN
etd-12232021-231927
Thesis title
Pharmacology and toxicology of dopaminergic compounds in pancreatic beta cells
Department
MEDICINA CLINICA E SPERIMENTALE
Course of study
FARMACOLOGIA E TOSSICOLOGIA CLINICA
Supervisors
relatore Prof. Scarselli, Marco
Keywords
  • insulin secretion
  • toxicity
  • beta cells
  • dopamine
Graduation session start date
10/01/2022
Availability
Withheld
Release date
10/01/2092
Summary
β-cells respond to dopamine (DA) and are equipped with a complete dopaminergic apparatus. Different human and rodent β-cell lines express dopamine receptors (D1-D5) and enzymes for dopamine production (tyrosine hydroxylase and aromatic amino-acid decarboxylase) and degradation (MAO-A and B). After production from its precursors, dopamine is stored in insulin vesicles via vesicular monoamine transporter-2 (VMAT-2) and co-released with insulin. β-cells also express transporters for dopamine (DAT) and its amino-acids precursors (LAT1 and 2). DA and dopamine agonists inhibit the release of insulin activating a negative feedback loop mediated by D2/D3 receptors. The downstream pathway responsible for this effect is probably Gi-mediated, with a scarce contribution for β-arrestin recruitment and activation. The source and in vivo role for DA on β-cells are still to be precisely characterized, most likely DA is locally produced and acts as an autocrine/paracrine signal. However, the existence of dopaminergic receptors on β-cells makes them a target for dopamine agonists and antagonists, and could explain some of their metabolic side effects. Moreover, given the similarity to dopaminergic neurons in terms of transporters and enzymes, we tested if classical parkinsonian neurotoxins Rotenone, 1-Methyl-4-phenylpyridinium (MPP +) and 6-Hydroxydopamine (6-OHDA) affect the function and viability of these cell types. rotenone is the most potent for reducing β-cells viability and altering mitochondrial structure and bioenergetics in the low nanomolar range, similar to that found in dopaminergic cell lines. MPP+ and 6-OHDA show similar effects but at higher concentration.
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