Differential G protein activation by the long and short isoforms of the dopamine D2 receptor

• DOI: 10.1111/bph.16388
• Publication Date: 2024-05-10T06:54:26Z
• Authors: David Reiner‐Link; Jakob Sture Madsen; David E. Gloriam; Hans Bräuner‐Osborne; Alexander S. Hauser
• Keywords: Endogenous agonist

Background and Purpose The dopamine D 2 receptor is expressed as a short (D2S) long (D2L) isoform with 29 additional amino acids in the third intracellular loop. D2S shows higher presynaptic expression than D2L isoform, decreased has recently been linked to an increased risk for schizophrenia. Here, we present first investigation, at level, of kinetic differences G protein activation profiles D2S, compared isoform. Experimental Approach We employed NanoBRET‐based approach dissociation interrogate time‐resolved coupling profile 3×HA‐tagged Gα i/o/z proteins vitro. Key Results Using agonist, observed more pronounced o z i by D2S. This differentiation was not which activated lower efficacy D2L. These signalling were preserved on second messenger level due expression. Expanding set seven full partial agonists showed these effects restricted but rather mutual, receptor‐associated property. Contrasting this trend, found that faster upon activation. Conclusion Implications findings highlight both are mechanistically able activate all non‐visual i/o proteins. Thereby, they add previous reports about isoform‐specificity certain specific cell types.