nNOS-mediated protein-protein interactions:promising targets for treating neurological and neuropsychiatric disorders

Neurological and neuropsychiatric disorders are one of the leading causes of disability worldwide and affect the health of billions of people.Nitric oxide(NO),a free gas with multitudinous bioactivities,is mainly produced from the oxidation of L-arginine by neuronal nitric oxide synthase(nNOS)in the brain.Inhibiting nNOS benefits a variety of neurological and neuropsychiatric disorders,including stroke,depression and anxiety disorders,posttraumatic stress disorder,Parkinson’s disease,Alzheimer’s disease,chronic pain,and drug addiction.Due to critical roles of nNOS in learning and memory and synaptic plasticity,direct inhibition of nNOS may cause severe side effects.Importantly,interactions of several proteins,including post-synaptic density 95(PSD-95),carboxyterminal PDZ ligand of nNOS(CAPON)and serotonin transporter(SERT),with the PSD/Disc-large/ZO-1 homologous(PDZ)domain of nNOS have been demonstrated to influence the subcellular distribution and activity of the enzyme in the brain.Therefore,it will be a preferable means to interfere with nNOS-mediated proteinprotein interactions(PPIs),which do not lead to undesirable effects.Herein,we summarize the current literatures on nNOS-mediated PPIs involved in neurological and neuropsychiatric disorders,and the discovery of drugs targeting the PPIs,which is expected to provide potential targets for developing novel drugs and new strategy for the treatment of neurological and neuropsychiatric disorders.

The Relative Deficiency of Potassium Ions in Nerve Cells Causes Abnormal Functions and Neurological and Mental Diseases

The difference of intracellular potassium (K+) and extracellular sodium (Na+) concentrations in nerve cells plays an important role in the functional activities of the nervous system. The maintenance of this difference mainly depends on the number and efficiency of Na, K-ATPase. However, due to the functional activity of nerve cells, this system often loses its balance. An undetectable phenomenon is the relative deficiency of potassium in nerve cells in specific brain regions or neural network structures, which leads to dysfunction of specific nerve cell populations or brain regions, thus leading to different types of neurological disorders or diseases. The relative deficiency of potassium ions in nerve cells may be caused by the competitive failure of nerve cells to effectively use potassium ions stored in the body, and the core reason may be related to insufficient potassium obtained through diet or effectively absorbed by the digestive system. Therefore, a simple strategy is to treat a patient by taking appropriate potassium orally. This paper presents a case with great success by using such a method to treat a patient with major depression.

nNOS and Neurological, Neuropsychiatric Disorders: A 20-Year Story

In the central nervous system,nitric oxide(NO),a free gas with multitudinous bioactivities,is mainly produced from the oxidation of L-arginine by neuronal nitric oxide synthase(nNOS).In the past 20 years,the studies in our group and other laboratories have suggested a significant involvement of nNOS in a variety of neurological and neuropsychiatric disorders.In particular,the interactions between the PDZ domain of nNOS and its adaptor proteins,including post-synaptic density 95,the carboxy-terminal PDZ ligand of nNOS,and the serotonin transporter,significantly influence the subcellular localization and functions of nNOS in the brain.The nNOS-mediated protein-protein interactions provide new attractive targets and guide the discovery of therapeutic drugs for neurological and neuropsychiatric disorders.Here,we summarize the work on the roles of nNOS and its association with multiple adaptor proteins on neurological and neuropsychiatric disorders.