Calcium signaling cascade links dopamine D1-D2 receptor heteromer to striatal BDNF production and neuronal growth

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 106; no. 50; pp. 21377 - 21382
• Main Authors: Hasbi, Ahmed, Fan, Theresa, Alijaniaram, Mohammad, Nguyen, Tuan, Perreault, Melissa L, O'Dowd, Brian F, George, Susan R
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences 15-12-2009; National Acad Sciences
• Subjects: Agonists; Animals; Behavioral neuroscience; Biological Sciences; Brain; Brain Chemistry; Brain-Derived Neurotrophic Factor - biosynthesis; Calcium; Calcium Signaling; Cell Differentiation; Cell growth; Corpus Striatum - cytology; Corpus Striatum - metabolism; Cytosol; Dopamine receptors; Maturation; Mice; Mice, Knockout; Neurogenesis; Neurons; Neurons - metabolism; Neurotransmitters; Nucleus Accumbens; Protein Multimerization; Receptors; Receptors, Dopamine D1 - metabolism; Receptors, Dopamine D2 - metabolism; Rodents; Schizophrenia
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.0903676106

Although the perturbation of either the dopaminergic system or brain-derived neurotrophic factor (BDNF) levels has been linked to important neurological and neuropsychiatric disorders, there is no known signaling pathway linking these two major players. We found that the exclusive stimulation of the dopamine D1-D2 receptor heteromer, which we identified in striatal neurons and adult rat brain by using confocal FRET, led to the activation of a signaling cascade that links dopamine signaling to BDNF production and neuronal growth through a cascade of four steps: (i) mobilization of intracellular calcium through Gq, phospholipase C, and inositol trisphosphate, (ii) rapid activation of cytosolic and nuclear calcium/calmodulin-dependent kinase IIα, (iii) increased BDNF expression, and (iv) accelerated morphological maturation and differentiation of striatal neurons, marked by increased microtubule-associated protein 2 production. These effects, although robust in striatal neurons from D5⁻/⁻ mice, were absent in neurons from D1⁻/⁻ mice. We also demonstrated that this signaling cascade was activated in adult rat brain, although with regional specificity, being largely limited to the nucleus accumbens. This dopaminergic pathway regulating neuronal growth and maturation through BDNF may have considerable significance in disorders such as drug addiction, schizophrenia, and depression.