The role in Regulatory of G proteins signaling (RGS) proteins in brain excitability

Document Type : Original Research

Author
S. Namvar
Department of Biology, Faculty of Basic Sciences, Azerbaijan Shahid Madani University, Tabriz, Iran
Abstract
Heterotrimeric G proteins involved in many transmembrane signaling in the nervous system. Regulation of the signaling speed of G proteins is done by different types of proteins. One of the most important types of these proteins are called, Regulatory of G proteins signaling Proteins (RGS), that increase the GTPase activity of Ga subunit of G proteins. These proteins have more than 30 members and are characterized by the existence of a region of 120 amino acids, which is called the RGS region Today, it has been determined in addition to increase GTPase activity, RGS proteins can also act as antagonists of effectors by competing with effector molecules to bind to active Gα Another is RGS proteins specifically and selectively regulate the function of receptors coupled to G proteins and ion channels and other signaling events. The RGS protein family has essential roles in GPCR signaling in the nervous system. At neuronal synapses, GPCRs, G proteins, and RGS proteins work with together to regulate key aspects of neurotransmitter release, synaptic transmission, and synaptic plasticity that are necessary for CNS physiology and behavior thereby affecting neuronal excitability in the central nervous system. Studies have shown that the levels of cAMP and protein kinase A in the brain of seizure patients are more different than those of healthy subjects that this mediated by G proteins signaling.

Keywords

1. Hosford, PS, Mosienko V, Kishi K, Jurisic G, Suewen K, Kinzel B, et al. CNS distribution, signalling properties and central effects of G-protein coupled receptor 4. Neuropharmacol. 2018; 138: 381-392.
2. Congreve M, Graaf C de, Swain N A, Tate C G. Impact of GPCR structures on drug discovery. Cell. 2020; 181 (1): 81-91
3. Cooper, J R, Floyd E B, Robert H R. The biochemical basis of neuropharmacology. Oxford University Press, USA, 2003.
4. Masuho I, Santhanam B, Brian S, John J G, Tesmer M, Madan B, Kirill A. .A global map of G protein signaling regulation by RGS proteins. Cell. 2020; 183(2): 503-521
5. T aymans JM, Wintmolders C, Te Riele P, Jurzak M, Groenewegen HJ, TLeysen JE, Langlois X. Detailed localization of regulator of G protein signaling 2 messenger ribonucleic acid and protein in the rat brain. Neurosci. 2002;114 : 39-53.
6. Stewart A, Fisher RA. Introduction: G protein-coupled receptors and RGS proteins. Prog. Mol. Biol. Transl. Sci. 2015; 133: 1-11.
7. Xie GX, Palmer PP, How regulators of G protein signaling achieve selective regulation. J Mol Biol. 2007; 366: 349-365.
8. Kim Y, and Sungho G. Regulators of G-protein signaling, RGS2 and RGS4, inhibit protease-activated receptor 4-mediated signaling by forming a complex with the receptor and Gα in live cells. Cell Commun Signal. 2020; 18 :1-13
9. Almutairi F, Jae-Kyung L, Balázs R. Regulator of G protein signaling 10: Structure, expression and functions in cellular physiology and diseases. Cell Signal. 2020; 75: 109765.
10. O’Brien J B, Joshua C W, David LR. Regulator of G-protein signaling (RGS) proteins as drug targets: Progress and future potentials. J Biol Chem. 2019; 294(49) : 18571-18585
11. Gerber K J, Katherine ES, John R H. Roles for regulator of G protein signaling proteins in synaptic signaling and plasticity. Mol Pharmacol. 2016; 89(2) : 273-286.‏
12. Alqinyah M, Shelley B H. Regulating the regulators: Epigenetic, transcriptional, and post-translational regulation of RGS proteins. Cell signal.2018; 42 : 77-87
13. Harbin H N, Bramlett S N, Miranda C M, Terzioglu G Hepler G R. RGS14 regulation of post-synaptic signaling and spine plasticity in brain. Int J Mol Sci. 2021; 22(13): 6823
14. Beckers P, Pierre J D, Emmanuel H. Modulation of Type 5 Metabotropic Glutamate Receptor-Mediated Intracellular Calcium Mobilization by Regulator of G Protein Signaling 4 (RGS4) in Cultured Astrocytes. Cells. 2024; 13(4) : 291.
15. Samadi, M, Hales C A, Lustberg D J, Farris S, Ross M R, Zhao M, et al. Mechanisms of mGluR‐dependent plasticity in hippocampal area CA2. Hippocampus. 2023; 33(6): 730-744.‏
16. Kleppisch T, Voigt V, Allmann DR, Offermanns S. Gαq-deficient mice lack metabotropic glutamate receptor-dependent long-term depression but show normal long-term potentiation in the hippocampal CA1 region. J Neurosci. 2001; 21: 4943-4948.
17. Garrido-Sanabria RE, Pacheco Otalora1 F L, Arshadmansab FM, Herrera B, Francisco S, Ermolinsky B. Impaired expression and function of group II metabotropic glutamate receptors in pilocarpine-treated chronically epileptic rats. Brain Res. 2008; 1240: 165-176.
18. Clark M C, Deborah J B. Arthropod D2 receptors positively couple with cAMP through the Gi/o protein family. Comparative Biochemistry and Physiology Part B: Biochem Mol Biol. 2007; 146 (1): 9-19.
19. Shen, C, Mao C, Xu C, Jin N, Zhang H, Shen D D, et al. Structural basis of GABAB receptor–Gi protein coupling. Nature. 2021; 594(7864): 594-598
20. Lopez-Mera M L, Neri-Bazan L, Rocha L. Low frequency stimulation modiries receptor binding in rat brain. Epilepsy Res. 2004; 59: 95-105.
21. Draper JC, Khoshouei M, Thal D M, Liang Y L, NguYen A TN, Furness SGB, et al. Structure of the adenosine-bound human adenosine A1 receptor–Gi complex. Nature. 2018; 558 (7711): 559-563.

22. О. I. Pisarenko1Studneva, I M, Veselova1 O M, Bahtin A A, Konovalova G G, Lankin V Z. The mechanisms of cardiac protection using a synthetic agonist of galanin receptors during chronic administration of doxorubicin. Acta Naturae. 2020; 12.1: 89.
23. Huang C C, Chen L Y, Liang C Y, Hsu S K. Role for cAMP and protein phosphatase in the presynaptic expression of mouse hippocampal mossy fibre depotentiation. J Physiol. 2002; 543: 767-787.
24. Chen H, Clark MA, Lambert NA. Endogenous RGS proteins regulate presynaptic and postsynaptic function: functional expression of RGS-insensitive Galpha subunits in central nervous system neurons. Methods Enzymol. 2004; 389 : 190-204.
25. Namvar, S., Fathollahi, Y., Javan, M., Zeraati, M., Mohammad-Zadeh, M., Shojaei, A., & Mirnajafi-Zadeh, J. The antiepileptogenic effect of low-frequency stimulation on perforant path kindling involves changes in regulators of G-protein signaling in rat. Journal of the Neurol Sci. 2017; 375: 450-459.
Pathobiology Reserach
Volume 26, Issue 1
November 2023
Pages 29-34