The Role of the Central Region of the Third Intracellular Loop of D1-Class Receptors in Signalling
The D1-class receptors (D1R, D5R) each possess distinct signaling characteristics; however, pharmacological selectivity between them remains elusive. The third intracellular loops (IL3) of D1R and D5R harbour divergent residues that may contribute to their individual signalling phenotypes. Here we...
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ndltd-LACETR-oai-collectionscanada.gc.ca-OOU-OLD.-230802013-04-05T03:21:10ZThe Role of the Central Region of the Third Intracellular Loop of D1-Class Receptors in SignallingCharrette, AndrewG protein-coupled receptorGPCRDopamineD1D5homology modeldeletionthird intracellular loopD1-class receptorThe D1-class receptors (D1R, D5R) each possess distinct signaling characteristics; however, pharmacological selectivity between them remains elusive. The third intracellular loops (IL3) of D1R and D5R harbour divergent residues that may contribute to their individual signalling phenotypes. Here we probe the function of central region of IL3 of D1R and D5R using deletion mutagenesis. Radioligand binding and whole cell cAMP assays suggest that the N-terminal and C-terminal moieties of the central IL3 oppositely contribute to the constitutive and agonist-dependant activity of D1-Class receptors. Whereas the N-terminal deletions ablated constitutive activity and decreased DA-induced activation, C-terminal deletions induced robust increases. These data, interpreted in concert with structural predictions generated from homology modeling implicate the central IL3 as playing an important role in the activation and subtype-specific characteristics of the D1-class receptors. This study may serve as a basis for the development of novel drugs targeting the central IL3 region.2012-07-17T07:59:28Z2012-07-17T07:59:28Z20122012-07-17Thèse / Thesishttp://hdl.handle.net/10393/23080en |
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NDLTD |
language |
en |
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topic |
G protein-coupled receptor GPCR Dopamine D1 D5 homology model deletion third intracellular loop D1-class receptor |
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G protein-coupled receptor GPCR Dopamine D1 D5 homology model deletion third intracellular loop D1-class receptor Charrette, Andrew The Role of the Central Region of the Third Intracellular Loop of D1-Class Receptors in Signalling |
description |
The D1-class receptors (D1R, D5R) each possess distinct signaling characteristics; however, pharmacological selectivity between them remains elusive. The third intracellular loops (IL3) of D1R and D5R harbour divergent residues that may contribute to their individual signalling phenotypes. Here we probe the function of central region of IL3 of D1R and D5R using deletion mutagenesis. Radioligand binding and whole cell cAMP assays suggest that the N-terminal and C-terminal moieties of the central IL3 oppositely contribute to the constitutive and agonist-dependant activity of D1-Class receptors. Whereas the N-terminal deletions ablated constitutive activity and decreased DA-induced activation, C-terminal deletions induced robust increases. These data, interpreted in concert with structural predictions generated from homology modeling implicate the central IL3 as playing an important role in the activation and subtype-specific characteristics of the D1-class receptors. This study may serve as a basis for the development of novel drugs targeting the central IL3 region. |
author |
Charrette, Andrew |
author_facet |
Charrette, Andrew |
author_sort |
Charrette, Andrew |
title |
The Role of the Central Region of the Third Intracellular Loop of D1-Class Receptors in Signalling |
title_short |
The Role of the Central Region of the Third Intracellular Loop of D1-Class Receptors in Signalling |
title_full |
The Role of the Central Region of the Third Intracellular Loop of D1-Class Receptors in Signalling |
title_fullStr |
The Role of the Central Region of the Third Intracellular Loop of D1-Class Receptors in Signalling |
title_full_unstemmed |
The Role of the Central Region of the Third Intracellular Loop of D1-Class Receptors in Signalling |
title_sort |
role of the central region of the third intracellular loop of d1-class receptors in signalling |
publishDate |
2012 |
url |
http://hdl.handle.net/10393/23080 |
work_keys_str_mv |
AT charretteandrew theroleofthecentralregionofthethirdintracellularloopofd1classreceptorsinsignalling AT charretteandrew roleofthecentralregionofthethirdintracellularloopofd1classreceptorsinsignalling |
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1716579590617432064 |