@article{e126ec739bd14450995bb95303b4ce72,
title = "Integrated regulation of PKA by fast and slow neurotransmission in the nucleus accumbens controls plasticity and stress responses",
abstract = "Cortical glutamate and midbrain dopamine neurotransmission converge to mediate striatum-dependent behaviors, while maladaptations in striatal circuitry contribute to mental disorders. However, the crosstalk between glutamate and dopamine signaling has not been entirely elucidated. Here we uncover a molecular mechanism by which glutamatergic and dopaminergic signaling integrate to regulate cAMP-dependent protein kinase (PKA) via phosphorylation of the PKA regulatory subunit, RIIβ. Using a combination of biochemical, pharmacological, neurophysiological, and behavioral approaches, we find that glutamate-dependent reduction in cyclin-dependent kinase 5 (Cdk5)-dependent RIIβ phosphorylation alters the PKA holoenzyme autoinhibitory state to increase PKA signaling in response to dopamine. Furthermore, we show that disruption of RIIβ phosphorylation by Cdk5 enhances cortico-ventral striatal synaptic plasticity. In addition, we demonstrate that acute and chronic stress in rats inversely modulate RIIβ phosphorylation and ventral striatal infusion of a small interfering peptide that selectively targets RIIβ regulation by Cdk5 improves behavioral response to stress. We propose this new signaling mechanism integrating ventral striatal glutamate and dopamine neurotransmission is important to brain function, may contribute to neuropsychiatric conditions, and serves as a possible target for the development of novel therapeutics for stress-related disorders.",
keywords = "Cdk5, PKA, RIIβ, dopamine, glutamate, plasticity, stress",
author = "Rachel Thomas and Adan Hernandez and Benavides, {David R.} and Wei Li and Chunfeng Tan and Alan Umfress and Florian Plattner and Ayanabha Chakraborti and Lucas Pozzo-Miller and Taylor, {Susan S.} and Bibb, {James A.}",
note = "Funding Information: We thank H. Ball (UT Southwestern Protein Chemistry Core) for peptides; I. Bowen and the UTSW morphology core for help with microscopy; D. Guzman and S. Birnbaum for technical advice; H. Shu for mass spectrometry, A. Kornev for help with modeling, the UTSW ARC for help with antibody generation. We also thank the SDHB Pheo Para Coalition and the Neuroendocrine Tumor Research Foundation for supporting our research. R. T. and J. A. B. conceptualization; R. T. A. H. D. R. B. W. L. C. T. and A. U. investigation; R. T. A. H. D. R. B. W. L. and A. U. formal analysis, R. T. writing–original draft; F. P. and S. S. T. methodology; F. P. L. P.-M. S. S. T. and J. A. B supervision; F. P. A. C. L. P.-M. S. S. T. and J. A. B. writing-review & editing; J. A. B. funding acquisition. R. T. is the recipient of the P. E. O. Scholar Award and received support from training grants DA7290 and MH076690. A. U. is supported by a T32 predoctoral training fellowship (5T32NS061788). This work was also supported by National Institutes of Health grants to W. L. (NS108508, NS097913, NS121542, NS120315), L. P.-M. (NS103089), S. S. T (1R35 GM130389), and J. A. B. (DA033485, MH116896, MH126948). Aspects of this work were also facilitated by pilot grant funding from the UAB Diabetes Research Center (NIH P30 DK-079626), the Yale Neuroproteomics Center (DA018343), the Breast Cancer Research Foundation of Alabama, and the UAB O'Neal Comprehensive Cancer Center (P30CA013148). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. Funding Information: We thank H. Ball (UT Southwestern Protein Chemistry Core) for peptides; I. Bowen and the UTSW morphology core for help with microscopy; D. Guzman and S. Birnbaum for technical advice; H. Shu for mass spectrometry, A. Kornev for help with modeling, the UTSW ARC for help with antibody generation. We also thank the SDHB Pheo Para Coalition and the Neuroendocrine Tumor Research Foundation for supporting our research. Funding Information: R. T. is the recipient of the P. E. O. Scholar Award and received support from training grants DA7290 and MH076690. A. U. is supported by a T32 predoctoral training fellowship (5T32NS061788). This work was also supported by National Institutes of Health grants to W. L. (NS108508, NS097913, NS121542, NS120315), L. P.-M. (NS103089), S. S. T (1R35 GM130389), and J. A. B. (DA033485, MH116896, MH126948). Aspects of this work were also facilitated by pilot grant funding from the UAB Diabetes Research Center ( NIH P30 DK-079626 ), the Yale Neuroproteomics Center ( DA018343 ), the Breast Cancer Research Foundation of Alabama , and the UAB O{\textquoteright}Neal Comprehensive Cancer Center ( P30CA013148 ). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. Publisher Copyright: {\textcopyright} 2022 The Authors",
year = "2022",
month = aug,
doi = "10.1016/j.jbc.2022.102245",
language = "English (US)",
volume = "298",
journal = "Journal of Biological Chemistry",
issn = "0021-9258",
publisher = "American Society for Biochemistry and Molecular Biology Inc.",
number = "8",
}