Differential G protein activation by the long and short isoforms of the dopamine D2 receptor
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Differential G protein activation by the long and short isoforms of the dopamine D2 receptor. / Reiner-Link, David; Madsen, Jakob Sture; Gloriam, David E.; Bräuner-Osborne, Hans; Hauser, Alexander S.
In: British Journal of Pharmacology, 2024.Research output: Contribution to journal › Journal article › Research › peer-review
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TY - JOUR
T1 - Differential G protein activation by the long and short isoforms of the dopamine D2 receptor
AU - Reiner-Link, David
AU - Madsen, Jakob Sture
AU - Gloriam, David E.
AU - Bräuner-Osborne, Hans
AU - Hauser, Alexander S.
N1 - Publisher Copyright: © 2024 The Authors. British Journal of Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.
PY - 2024
Y1 - 2024
N2 - Background and Purpose: The dopamine D2 receptor is expressed as a short (D2S) and a long (D2L) isoform with 29 additional amino acids in the third intracellular loop. The D2S isoform shows higher presynaptic expression than the D2L isoform, and decreased D2S expression has recently been linked to an increased risk for schizophrenia. Here, we present the first investigation, at receptor isoform level, of kinetic differences in the G protein activation profiles of the D2S, compared with the D2L isoform. Experimental Approach: We employed a NanoBRET-based approach to G protein dissociation to interrogate the time-resolved coupling profile of 3×HA-tagged D2L and D2S to Gαi/o/z proteins in vitro. Key Results: Using dopamine as a D2 receptor agonist, we observed a more pronounced activation of Gαo and Gαz than Gαi proteins by D2L compared with D2S. This differentiation was not observed for D2S, which activated Gαo and Gαz with lower efficacy than D2L. These signalling differences were preserved on second messenger level and were not due to differences in receptor expression. Expanding to a set of seven full and partial D2 receptor agonists showed these effects were not restricted to dopamine but rather a mutual, receptor-associated property. Contrasting this trend, we found that D2S activated G proteins faster than D2L upon full receptor activation. Conclusion and Implications: The findings highlight that both D2L and D2S are mechanistically able to activate all non-visual Gαi/o proteins. Thereby, they add to previous reports about isoform-specificity to certain Gαi/o proteins observed in specific cell types.
AB - Background and Purpose: The dopamine D2 receptor is expressed as a short (D2S) and a long (D2L) isoform with 29 additional amino acids in the third intracellular loop. The D2S isoform shows higher presynaptic expression than the D2L isoform, and decreased D2S expression has recently been linked to an increased risk for schizophrenia. Here, we present the first investigation, at receptor isoform level, of kinetic differences in the G protein activation profiles of the D2S, compared with the D2L isoform. Experimental Approach: We employed a NanoBRET-based approach to G protein dissociation to interrogate the time-resolved coupling profile of 3×HA-tagged D2L and D2S to Gαi/o/z proteins in vitro. Key Results: Using dopamine as a D2 receptor agonist, we observed a more pronounced activation of Gαo and Gαz than Gαi proteins by D2L compared with D2S. This differentiation was not observed for D2S, which activated Gαo and Gαz with lower efficacy than D2L. These signalling differences were preserved on second messenger level and were not due to differences in receptor expression. Expanding to a set of seven full and partial D2 receptor agonists showed these effects were not restricted to dopamine but rather a mutual, receptor-associated property. Contrasting this trend, we found that D2S activated G proteins faster than D2L upon full receptor activation. Conclusion and Implications: The findings highlight that both D2L and D2S are mechanistically able to activate all non-visual Gαi/o proteins. Thereby, they add to previous reports about isoform-specificity to certain Gαi/o proteins observed in specific cell types.
KW - D2L
KW - D2S
KW - dopamine D2 receptor
KW - G protein activation
KW - splice variants
U2 - 10.1111/bph.16388
DO - 10.1111/bph.16388
M3 - Journal article
C2 - 38725357
AN - SCOPUS:85192553660
JO - British Journal of Pharmacology
JF - British Journal of Pharmacology
SN - 0007-1188
ER -
ID: 392449877