Kinin receptor B2 participation in the nervous system with emphasis on the dopaminergic circuit

• Grant number: 19/07005-4
• Support type: Research Grants - Young Investigators Grants
• Duration: April 01, 2021 - March 31, 2026
• Field of knowledge: Biological Sciences - Physiology
• Principal researcher: Frederick Wasinski
• Grantee: Frederick Wasinski
• Home Institution: Instituto de Ciências Biomédicas (ICB). Universidade de São Paulo (USP). São Paulo , SP, Brazil
• Assoc. researchers: Carolina Demarchi Munhoz ; Jose Donato Junior ; Michael Bader ; Ronaldo de Carvalho Araújo
• Associated scholarship(s): 21/09559-7 - Kinin B2 receptor ablation in catecholaminergic neurons, BP.IC; 21/04039-5 - Kinin receptor B2 participation in the nervous system with emphasis on the dopaminergic circuit, BP.JP

Abstract

The kallikrein-kinins system is a system that evolves a set of blood proteins that acts in many biological processes, such as inflammatory response, blood pressure control and pain. The physiological effects of kinins are mediated by two transmembrane receptors coupled to G protein, known as B1 and B2 receptors, and both are regulated under pathological conditions involved in pro-inflammatory effects. Recently our group showed that kinins participate in the processes of cell proliferation in the hippocampus, after the animals are submitted to a voluntary wheel, as well as changes in performance during physical activity. One hypothesis for this effect would be an interrelationship between the dopaminergic pathway and the kinin receptors, since dopamine plays an important role in the control of locomotor activity. The dopaminergic pathway acts on various brain functions such as locomotor activity, behavioral, cognitive, motivation and reward. Dopamine D2 receptors can act as self-receptors where they perceive the excessive flow of dopamine from the synapse and reduce dopaminergic tone, decreasing the synthesis of dopamine in the presynaptic neuron, reducing the rate of neuronal discharge and the release of dopamine. Animals deficient for the D2 receptor showed a decrease in running time and became obese. Data from the literature show that both D2 dopaminergic receptors and kinin B2 receptors are coupled to G protein, and the activation of one of these receptors may affect the response of the other through this cellular interaction. However, the real importance of the B2 receptor on the dopaminergic circuit has never been explored until then. Our hypothesis is that the interaction between these two systems on G protein signaling is one of the mechanisms involved in the decrease in the locomotor activity of kinin knockout animals. To investigate a possible interrelationship between the kinin B2 receptor and the dopaminergic pathway, we will generate genetically modified animals using CreLoxP technology with specific inactivation of the B2 receptor in dopaminergic neurons (Bdkrb2 flox/flox, TH Cre) or in cells which express the dopamine D2 receptor (Bdkrb2 flox/flox, Drd2Cre). We will also study B2-deficient mice in the nervous system, specifically in the forebrain and pyramidal neurons of the hippocampus (Bdkrb2 flox/flox CamK2a Cre). To better understand the relationship between kinin and dopamine, we will evaluate body and metabolic changes in the studied groups, as well as tests of voluntary physical activity and physical training. Since the dopaminergic pathway modulates various functions in the brain, tests such as food preference (taste test and hyperlipid diet) and behavioral tests (memory, anxiety and motor coordination) will be performed. Following these tests, molecular analyzes of specific brain areas of genes involved in the production of new neurons and in the production of dopamine will be done. With our results, we hope to better understand the mechanisms involved in the interaction between the kinin B2 receptor and the dopaminergic pathway. (AU)