Neurological Functions of the Masterswitch Protein Kinase – GSK-3

Book excerpt: The functions of the brain that allow us to think, feel, move, and perceive the world are the result of an exchange of information within a network composed of millions of specialized cells called neurons and glia. Neurons use neurotransmitters and other extracellular messengers to communicate with each other, and to constantly update and re-organize their network of connections in a process known as neural plasticity. In order to respond to these extracellular signals, neurons are equipped with specialized receptors that can recognize a single neurotransmitter a bit like a lock would recognize a key. They do this by activating or inhibiting a class of specialized signaling proteins and second messengers. Typically, signaling proteins are themselves organized in networks or pathways in which they activate or inhibit each other in order to integrate the mass of information received by a single cell and to regulate the biological functions of this cell. As we can see, rather than simply being a network of neurons, the brain can be seen as a sort of “Russian doll” in which each neuron is at the same time a part of networks with other neurons and the receptacle of many networks composed of signaling proteins. Two individual genes encode two paralogous signaling proteins: Glycogen Synthase Kinase -3 alpha and beta (GSK-3a, GSK-3b), named for its ability to phosphorylate a key metabolic enzyme of glycogen synthesis, glycogen synthase. This unique “glamour and gloom” protein kinase, has been intriguing many researches for over 30 years by its unusual features, still unknown mechanisms of its activation, its regulation by multiple “key” intracellular pathways, and its capacity to influence the functions of many substrates. Since GSK-3 was discovered, there has been significant progress in elucidating its regulatory roles in the neuron and the structure and functions of the brain. Lithium has been used as a gold standard in the treatment of bipolar disorder for 60 years; and “GSK-3’s renaissance” in psychiatry began with the discovery of GSK-3 as lithium's intracellular target. Since then, GSK3 has been implicated in the pathogenesis of mood disorders, schizophrenia, Alzheimer’s disease, ADHD, multiple sclerosis, Fragile X syndrome and Huntington disease. Connections to these and other diseases has led over the last 10 years to the generation of multiple types of GSK-3 inhibitors as promising therapeutic treatments for the aforementioned pathological conditions. During last couple years new genetic models have been generated, including conventional and conditional mouse models, allowing the discovery of new roles of GSK-3 in the mechanism of neurotransmitter action, neurodevelopment, learning and memory formation, GSK-3’s gene - effect on mouse behavior, and other functions. Thus, GSK-3 has been well-established as an intracellular second messenger for several neurotransmitter systems, and as an important therapeutic target of mood stabilizers, antipsychotics and psychomimetic drugs. The proposed Specific Topic for Frontiers in Neuroscience will be focused on the latest advances from leading laboratories in this area, subdivided into 5 topics: (1) GSK-3 history, mechanism of regulation, substrate specificity and comparison between the brain function of two GSK-3 genes through new animal models and cell biology approaches; (2) role of GSK-3 in neurodevelopment and neuronal structure; (3) involvement of GSK-3 in synaptic functions, learning and memory, and in serotonin and dopamine pathways; (4) role of GSK-3 in neuroinflammation, and application to the pathogenesis of multiple sclerosis, AD, schizophrenia, Fragile X, brain tumors, stroke and bipolar disorder; (5) development of GSK-3 inhibitors and their application in psychiatry, including special discussion about the mechanism of lithium action.