Disease-Associated Dopamine Receptor D2 Variants Exhibit Functional Consequences Depending on Different Heterotrimeric G-Protein Subunit Combinations
Abstract
:1. Introduction
2. Materials and Methods
2.1. Chemicals
2.2. Molecular Biology
2.3. Cell Culture and Transfection
2.4. G-Protein Signaling Assay
2.5. β-Arrestin 2 Signaling Assay
2.6. Data Analysis and Statistics
3. Results
3.1. β-Arrestin 2 Recruitment of the WT, I212F, and M345R
3.2. WT, I212F, and M345R G-Protein Activation
3.3. G-Protein Expression in Mouse and Human Brains
3.4. Effect of I212F and M345R on GαoA and αi1 in Combination with β1 and β2 and γ3 and γ7
4. Conclusions
Author Contributions
Funding
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
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β-arrestin 2 | WT | I212F | M345R | Anova | n/N | ||
---|---|---|---|---|---|---|---|
pEC50 | 9.08 ± 0.10 | 8.17 ± 0.15 | p = 0.036 | 6.56 ± 0.57 | p < 0.001 | F(2,45) = 22.99, p < 0.001 | 9/3 |
Basal activity | 2.21 ± 1.02 | 0.64 ± 1.21 | p = 0.661 | 14.60 ±1.89 | p < 0.001 | F(2,31) = 28.40, p < 0.001 | 9/3 |
Emax | 86.60 ± 2.47 | 78.32 ± 3.75 | p = 0.134 | 51.97 ± 3.96 | p < 0.001 | F(2,44) = 29.99, p < 0.001 | 9/3 |
pEC50 | |||||||||||
---|---|---|---|---|---|---|---|---|---|---|---|
Gαi1, β3, γ9 | Gαi2, β3, γ9 | Gαi3, β3, γ9 | GαoA, β3, γ8 | GαoB, β3, γ8 | n/N | ||||||
WT | 6.95 ± 0.04 | 7.72 ± 0.09 | 6.90 ± 0.02 | 0.18 ± 0.21 | 7.38 ± 0.08 | 9/3 | |||||
I212F | 7.27 ± 0.08 | p = 0.122 | 8.76 ± 0.41 | p = 0.010 | 7.63 ± 0.07 | p < 0.001 | nd | - | 7.93 ± 0.31 | p = 0.110 | 9/3 |
M345R | 7.80 ± 0.18 | p < 0.001 | 9.03 ± 0.11 | p = 0.002 | 9.13 ± 0.18 | p < 0.001 | nd | - | nd | - | 9/3 |
Anova | F(2,24) = 13.13, p < 0.001 | F(2,19) = 8.70, p = 0.002 | F(2,19) = 161.40, p < 0.001 | - | t-test | ||||||
Basal activity | |||||||||||
Gαi1, β3, γ9 | Gαi2, β3, γ9 | Gαi3, β3, γ9 | GαoA, β3, γ8 | GαoB, β3, γ8 | n/N | ||||||
WT | 0.00 ± 3.16 | 0.00 ± 20.60 | 0.00 ± 1.53 | 0.00 ± 2.01 | 0.00 ± 2.89 | 9/3 | |||||
I212F | 43.99 ± 2.65 | p < 0.001 | −26.09 ± 8.27 | p = 0.023 | −11.57 ± 7.46 | p = 0.639 | 102.20 ± 7.99 | p < 0.001 | 64.05 ± 13.81 | p = 0.002 | 9/3 |
M345R | 83.35 ± 3.50 | p < 0.001 | 20.60 ± 7.04 | p = 0.111 | 46.66 ± 15.85 | p = 0.007 | 115.50 ± 5.66 | p < 0.001 | 116.60 ± 14.66 | p < 0.001 | 9/3 |
Anova | F(2,24) = 178.20, p < 0.001 | F(2,21) = 10.43, p < 0.001 | F(2,24) = 9.22, p = 0.001 | F(2,24) = 119.99, p < 0.001 | F(2,24) = 24.72, p < 0.001 | ||||||
Emax | |||||||||||
Gαi1, β3, γ9 | Gαi2, β3, γ9 | Gαi3, β3, γ9 | GαoA, β3, γ8 | GαoB, β3, γ8 | n/N | ||||||
WT | 98.53 ± 2.42 | 100.90 ± 1.66 | 102.56 ± 0.88 | 102.93 ± 1.97 | 103.32 ± 1.70 | 9/3 | |||||
I212F | 107.67 ± 3.68 | p = 0.384 | 42.42 ± 3.27 | p < 0.001 | 102.25 ± 3.28 | p = 0.997 | 155.86 ± 2.41 | p < 0.001 | 132.32 ± 13.54 | p = 0.055 | 9/3 |
M345R | 144.54 ± 8.07 | p < 0.001 | 105.79 ± 6.79 | p = 0.591 | 125.18 ± 6.23 | p < 0.001 | 172.24 ± 3.84 | p < 0.001 | 175.62 ± 4.66 | p < 0.001 | 9/3 |
Anova | F(2,24) = 21.06, p < 0.001 | F(2,18) = 74.34, p < 0.001 | F(2,21) = 12.31, p < 0.001 | F(2,23) = 161.90, p < 0.001 | F(2,20) = 12.18, p < 0.001 |
pEC50 | |||||||||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|---|
GαoA, β1, γ7 | GαoA, β1, γ3 | Gαi1, β1, γ7 | GαoA, β2, γ7 | GαoA, β2, γ3 | Gαi1, β2, γ7 | n/N | |||||||
WT | 7.80 ± 0.02 | 7.99 ± 0.06 | 8.10 ± 0.38 | 7.64 ± 0.06 | 8.72 ± 0.26 | 7.18 ± 0.14 | 9/3 | ||||||
I212F | 8.40 ± 0.09 | p < 0.001 | 9.00 ± 0.38 | p = 0.011 | 8.09 ± 0.18 | p = 0.999 | 8.42 ± 0.29 | p = 0.050 | 9.65 ± 0.41 | p = 0.415 | 7.67 ± 0.52 | p = 0.289 | 9/3 |
M345R | nd | nd | 8.95 ± 0.18 | p = 0.091 | nd | nd | nd | 9/3 | |||||
Anova | t-test | t-test | F(2,20) = 2.84, p = 0.082 | t-test | t-test | t-test | |||||||
Basal activity | |||||||||||||
GαoA, β1, γ7 | GαoA, β1, γ3 | Gαi1, β1, γ7 | GαoA, β2, γ7 | GαoA, β2, γ3 | Gαi1, β2, γ7 | n/N | |||||||
WT | 0.00 ± 1.86 | 0.00 ± 1.71 | 0.00 ± 5.80 | 0.00 ± 4.08 | 0.00 ± 2.89 | 0.00 ± 2.23 | 9/3 | ||||||
I212F | 52.37 ± 11.81 | p = 0.005 | 27.64 ± 8.48 | p = 0.002 | 23.08 ± 8.07 | p = 0.440 | 46.82 ± 19.93 | p = 0.062 | 95.13 ± 5.33 | p < 0.001 | 41.62 ± 7.92 | p = 0.334 | 9/3 |
M345R | 111.87 ± 15.14 | p < 0.001 | 88.30 ± 3.16 | p < 0.001 | 133.67 ± 23.27 | p < 0.001 | 131.34 ± 15.34 | p < 0.001 | 145.76 ± 11.83 | p < 0.001 | 122.23 ± 31.67 | p < 0.001 | 9/3 |
Anova | F(2,24) = 25.26, p < 0.001 | F(2,24) = 72.21, p < 0.001 | F(2,24) = 23.91, p < 0.001 | F(2,24) = 20.48, p < 0.001 | F(2,24) = 93.01, p < 0.001 | F(2,21) = 9.72, p < 0.001 | |||||||
Emax | |||||||||||||
GαoA, β1, γ7 | GαoA, β1, γ3 | Gαi1, β1, γ7 | GαoA, β2, γ7 | GαoA, β2, γ3 | Gαi1, β2, γ7 | n/N | |||||||
WT | 101.38 ± 2.46 | 105.43 ± 3.25 | 117.75 ± 7.99 | 107.36 ± 4.07 | 107.50 ± 1.82 | 112.01 ± 8.96 | 9/3 | ||||||
I212F | 117.21 ± 11.89 | p = 0.532 | 111.57 ± 10.26 | p = 0.753 | 83.23 ± 4.85 | p = 0.194 | 152.83 ± 16.34 | p = 0.125 | 168.10 ± 6.70 | p < 0.001 | 141.98 ± 9.34 | p = 0.068 | 9/3 |
M345R | 141.65 ± 15.92 | p = 0.039 | 127.29 ± 4.23 | p = 0.081 | 184.23 ± 24.78 | p = 0.008 | 153.16 ± 33.17 | p = 0.176 | 166.43 ± 18.07 | p < 0.001 | 269.70 ± 8.12 | p < 0.001 | 9/3 |
Anova | F(2,21) = 3.08, p = 0.065 | F(2,22) = 2.36, p = 0.118 | F(2,22) = 11.54, p < 0.001 | F(2,21) = 2.30, p = 0.125 | F(2,22) = 13.22, p < 0.001 | F(2,17) = 83.76, p < 0.001 |
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Niebrügge, N.; Trovato, O.; Praschberger, R.; Lieb, A. Disease-Associated Dopamine Receptor D2 Variants Exhibit Functional Consequences Depending on Different Heterotrimeric G-Protein Subunit Combinations. Biomedicines 2025, 13, 46. https://doi.org/10.3390/biomedicines13010046
Niebrügge N, Trovato O, Praschberger R, Lieb A. Disease-Associated Dopamine Receptor D2 Variants Exhibit Functional Consequences Depending on Different Heterotrimeric G-Protein Subunit Combinations. Biomedicines. 2025; 13(1):46. https://doi.org/10.3390/biomedicines13010046
Chicago/Turabian StyleNiebrügge, Nele, Olga Trovato, Roman Praschberger, and Andreas Lieb. 2025. "Disease-Associated Dopamine Receptor D2 Variants Exhibit Functional Consequences Depending on Different Heterotrimeric G-Protein Subunit Combinations" Biomedicines 13, no. 1: 46. https://doi.org/10.3390/biomedicines13010046
APA StyleNiebrügge, N., Trovato, O., Praschberger, R., & Lieb, A. (2025). Disease-Associated Dopamine Receptor D2 Variants Exhibit Functional Consequences Depending on Different Heterotrimeric G-Protein Subunit Combinations. Biomedicines, 13(1), 46. https://doi.org/10.3390/biomedicines13010046