MSN

Researchers discover that the phosphorylation of a newly identified protein kinase substrate downstream of the dopamine signaling pathway regulates the brain reward behavior. The nucleus accumbens, part of the basal ganglia in the brain, is composed of neurons controlled by glutamate and dopamine. Dopamine regulates memory and learning, motor functions, and emotional behavior for motivation and reward. Researchers from Japan have now discovered that dopamine increases neuronal excitability via the phosphorylation of a voltage-gated potassium channel subfamily member (KCNQ2), promoting reward behavior in mice. Thus, KCNQ2 is a potential therapeutic target for the treatment of several psychiatric disorders. One part of the basal ganglia, known as the nucleus accumbens (NAc), is composed of medium spiny neurons (MSNs). The MSNs, in which the dopamine D1 receptor (D1R) and dopamine D2 receptor (D2R) express, are controlled by neurotransmitters -- glutamate and dopamine. Dopamine is an organic chemical that regulates memory and learning, motor functions, and emotional behavior for motivation and reward. On increasing the excitability of D1R-MSNs, dopamine promotes glutamate-induced responses, leading to a reward behavior, i.e., feelings of accomplishment and pleasure associated with completion of certain tasks. It is known that the molecular mechanism underlying this reward behavior involves a signaling cascade that increases the "phosphorylation" (the attachment of a phosphate group) of protein kinase A (PKA) substrates. Subsequently, the extracellular signal-regulated kinase (ERK), such as a downstream effector of PKA, modulates the excitability of D1R MSNs and in turn, the reward behavior. Recently, a team of researchers, including Assistant Professor Daisuke Tsuboi and Professor Kozo Kaibuchi of the Fujita Health University, and Dr. Nambu Atsushi and Dr. Hiromi Sano of the National Institute of Physiological Sciences in Japan, identified an ERK phospsho-substrate known as potassium voltage-gated channel subfamily Q member 2 (KCNQ2). Although certain studies have highlighted the role of KCNQ2 channels in MSN excitability, the details of the mechanism are still unclear. Now, Dr. Tsuboi and his team have investigated the mechanism through which ERK regulates KCNQ2 activity and affects dopamine signaling. "Dysfunctional dopamine signaling is implicated in several neuropsychological disorders, including Parkinson's disease, drug addiction, and schizophrenia. Therefore, understanding the underlying pathway is crucial for treating several psychiatric diseases," Dr. Tsuboi remarks while discussing the motivation behind the study, which was published in Volume 40, Issue 10 of Cell Reports on September 6, 2022. The team conducted experiments and mice and observed that the activation of D1R receptors with an agonist inhibited KCNQ-dependent currents and led to increased D1R-MSN firing rates in NAc slices of mice brains. Interestingly, MSN firing was halted on inhibiting ERK, suggesting its involvement in the process. Further analyses confirmed that the direct phosphorylation of KCNQ2 by ERK occurs through the activation of the dopamine signaling pathway in the NAc of mice. Next, the team noted that ERK-mediated phosphorylation of KCNQ2 decreased its channel activity. Moreover, the conditional deletion of the Kcnq2 gene in the D1R-MSNs of mice reduced the inhibitory effect of dopamine on the KCNQ current, enhancing neuronal excitability and reward behavior. These effects were rescued when the Kcnq2 gene was re-introduced, but not when its phospho-deficient mutant gene was introduced. This implies that dopamine signaling negatively regulates the currents via KNCQ phosphorylation. Based on these findings, the team proposed the following mechanism: Dopamine acts on D1R-MSNs to activate the ERK pathway that induces the phosphorylation of KCNQ2. This decreases the channel activity of KCNQ, which increases cell excitability and promotes reward behavior in the presence of glutamate. So, what are the long-term applications of these findings? Dr. Kaibuchi explains, "Mood disorders such as depression show signs associated with dysfunction of the reward system circuits in the brain. Hence, drugs modulating the dopamine-KCNQ2 pathway can be potential therapeutic targets for drug addiction and mood disorders. This study has highlighted KCNQ2 as a potential target for such psychiatric diseases." Here's hoping that these findings improve our understanding of the dopamine signaling pathway and its association with diverse emotional states.

DUBLIN, June 14, 2022 /PRNewswire/ -- The "Middle East Respiratory Syndrome coronavirus S Protein Drugs in Development by Therapy Areas and Indications, Stages, MoA, RoA, Molecule Type and Key Players" report has been added to ResearchAndMarkets.com's offering. Middle East Respiratory Syndrome coronavirus S Protein (Spike Protein) Drugs in Development by Therapy Areas and Indications, Stages, MoA, RoA, Molecule Type and Key Players report provides in depth analysis on Middle East Respiratory Syndrome coronavirus S Protein (Spike Protein) targeted pipeline therapeutics. The report provides comprehensive information complete with Analysis by Indications, Stage of Development, Mechanism of Action (MoA), Route of Administration (RoA) and Molecule Type. The report also covers the descriptive pharmacological action of the therapeutics, its complete research and development history and latest news and press releases. Additionally, the report analyses the pipeline products across relevant therapy areas under development and provides an overview of key players involved in Middle East Respiratory Syndrome coronavirus S Protein (Spike Protein) targeted therapeutics development and features dormant and discontinued projects. The report helps in identifying and tracking emerging players in the market and their portfolios, enhances decision making capabilities and helps to create effective counter strategies to gain competitive advantage. Scope The report provides a snapshot of the Global therapeutic landscape for Middle East Respiratory Syndrome coronavirus S Protein (Spike Protein) The report reviews Middle East Respiratory Syndrome coronavirus S Protein (Spike Protein) targeted therapeutics under development by companies and universities/research institutes based on information derived from company and industry-specific sources The report covers pipeline products based on various stages of development ranging from pre-registration till discovery and undisclosed stages The report features descriptive drug profiles for the pipeline products which includes, Product Description, Descriptive Mechanism of Action (MoA), Research and Development (R&D) brief, Licensing and Collaboration details & Other Developmental Activities The report reviews key players involved in Middle East Respiratory Syndrome coronavirus S Protein (Spike Protein) targeted therapeutics and enlists all their major and minor projects The report assesses Middle East Respiratory Syndrome coronavirus S Protein (Spike Protein) targeted therapeutics based on Mechanism of Action (MoA), Route of Administration (RoA) and Molecule Type The report summarizes all the dormant and discontinued pipeline projects The report reviews latest news and deals related to Middle East Respiratory Syndrome coronavirus S Protein (Spike Protein) targeted therapeutics Key Topics Covered: Introduction Report Coverage Target - Overview Target - Therapeutics Development Products under Development by Stage of Development Products under Development by Therapy Area Products under Development by Indication Products under Development by Companies Products under Development by Universities/Institutes Target - Therapeutics Assessment Assessment by Mechanism of Action Assessment by Route of Administration Assessment by Molecule Type Target - Companies Involved in Therapeutics Development Target - Dormant Products Target - Discontinued Products Target - Product Development Milestones Featured News & Press Releases Appendix For more information about this report visit Media Contact: Research and Markets Laura Wood, Senior Manager [email protected] For E.S.T Office Hours Call +1-917-300-0470 For U.S./CAN Toll Free Call +1-800-526-8630 For GMT Office Hours Call +353-1-416-8900 U.S. Fax: 646-607-1904 Fax (outside U.S.): +353-1-481-1716 SOURCE Research and Markets