Use this URL to cite or link to this record in EThOS: http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.626805
Title: Multiple dopamine signalling pathways antagonize RHO-1 signalling in the nervous system
Author: Bryon, K. H. R.
ISNI:       0000 0004 5363 7304
Awarding Body: University College London (University of London)
Current Institution: University College London (University of London)
Date of Award: 2014
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Abstract:
Alterations in RhoA (RHO-1) signalling cause neuronal signalling defects in both mammals and C. elegans. In the case of C. elegans, exaggerated RHO-1 signalling in cholinergic neurons (nRHO-1*) has numerous effects that include increased release of acetylcholine (ACh) and exaggerated body curvature during locomotion. A suppressor screen identified the mutation, nz99, that suppresses nRHO-1* exaggerated curvature, but not increased ACh release. Non-neuronal defects caused by heat-shock, expression of RHO-1* (sterility, death, tail-swelling and protruding vulva) were not suppressed, suggesting that DAT-1 is required only for RHO-1 neuronal signaling. Whole genome sequencing and rescue experiments identified the nz99 suppressor as a mutation in the dopamine transporter DAT-1. DAT-1 is a negative regulator of dopamine (DA) in both mammals and C. elegans by transporting extracellular DA into cells. dat-1 mutations were unable to suppress nRHO-1* locomotion defects when DA synthesis was inhibited either pharmacologically, using the drug reserpine, or genetically by a cat-2, (tyrosine hydroxylase) mutation. This is consistent with a model in which elevated DA signaling acts to inhibit the locomotion defects of nRHO-1*. Exogenous DA causes a dose dependent slowing of locomotion in C. elegans, and this was suppressed by nRHO-1*. Thus nRHO-1* and DA co-suppress each other's locomotion behaviours, suggesting that DA and RHO-1 signalling act in parallel to control locomotion. C. elegans possess at least four DA receptors of the G protein coupled class (DOP-1-4) that fall into either the D1 (DOP-1, 4) or the D2 class (DOP-2, 3). All four receptors are required for elevated DA signaling to suppress nRHO-1* locomotion defects. In other studies, the D1 and D2 classes of DA receptor have been shown to act antagonistically in controlling locomotive behaviours including, swimming, basal slowing and paralysis. My data suggests that a co-ordinated DA response that is mediated by multiple DA receptors, possibly acting in numerous cell types, also acts to modulate locomotion in C. elegans possibly by altering both small synaptic vesicle and dense core vesicle release.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID: uk.bl.ethos.626805  DOI: Not available
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