The cyclin G-associated kinase (GAK) inhibitor SGC-GAK-1 inhibits neurite outgrowth and synapse formation. 2022

Jun Egawa, and Reza K Arta, and Vance P Lemmon, and Melissa Muños-Barrero, and Yan Shi, and Michihiro Igarashi, and Toshiyuki Someya
Department of Psychiatry, School of Medicine, and Graduate School of Medical and Dental Sciences, Niigata University, 757 Asahimachi Dori-Ichibancho, Chuo-ku, Niigata, 951-8510, Japan. jeg5414@med.niigata-u.ac.jp.

Protein kinases are responsible for protein phosphorylation and are involved in important signal transduction pathways; however, a considerable number of poorly characterized kinases may be involved in neuronal development. Here, we considered cyclin G-associated kinase (GAK) as a candidate regulator of neurite outgrowth and synaptogenesis by examining the effects of the selective GAK inhibitor SGC-GAK-1. SGC-GAK-1 treatment of cultured neurons reduced neurite length and decreased synapse number and phosphorylation of neurofilament 200-kDa subunits relative to the control. In addition, the related kinase inhibitor erlotinib, which has distinct specificity and potency from SGC-GAK-1, had no effect on neurite growth, unlike SGC-GAK-1. These results suggest that GAK may be physiologically involved in normal neuronal development, and that decreased GAK function and the resultant impaired neurite outgrowth and synaptogenesis may be related to neurodevelopmental disorders.

UI MeSH Term Description Entries
D000071446 Neuronal Outgrowth Formation of neuronal processes (AXONS; NEURITES) toward a target cell. Axon Outgrowth,Neurite Outgrowth
D013569 Synapses Specialized junctions at which a neuron communicates with a target cell. At classical synapses, a neuron's presynaptic terminal releases a chemical transmitter stored in synaptic vesicles which diffuses across a narrow synaptic cleft and activates receptors on the postsynaptic membrane of the target cell. The target may be a dendrite, cell body, or axon of another neuron, or a specialized region of a muscle or secretory cell. Neurons may also communicate via direct electrical coupling with ELECTRICAL SYNAPSES. Several other non-synaptic chemical or electric signal transmitting processes occur via extracellular mediated interactions. Synapse
D016213 Cyclins A large family of regulatory proteins that function as accessory subunits to a variety of CYCLIN-DEPENDENT KINASES. They generally function as ENZYME ACTIVATORS that drive the CELL CYCLE through transitions between phases. A subset of cyclins may also function as transcriptional regulators. Cyclin
D016501 Neurites In tissue culture, hairlike projections of neurons stimulated by growth factors and other molecules. These projections may go on to form a branched tree of dendrites or a single axon or they may be reabsorbed at a later stage of development. "Neurite" may refer to any filamentous or pointed outgrowth of an embryonal or tissue-culture neural cell. Neurite
D047428 Protein Kinase Inhibitors Agents that inhibit PROTEIN KINASES. Protein Kinase Inhibitor,Inhibitor, Protein Kinase,Inhibitors, Protein Kinase,Kinase Inhibitor, Protein,Kinase Inhibitors, Protein
D056746 Cyclin G A cyclin subtype that is found associated with CYCLIN-DEPENDENT KINASE 5; cyclin G associated kinase, and PROTEIN PHOSPHATASE 2.
D017869 Cyclic GMP-Dependent Protein Kinases A group of cyclic GMP-dependent enzymes that catalyze the phosphorylation of SERINE or THREONINE residues of proteins. Guanosine Cyclic Monophosphate-Dependent Protein Kinase,Guanosine Cyclic Monophosphate-Dependent Protein Kinases,cGMP-Dependent Protein Kinase,cGMP-Dependent Protein Kinases,Cyclic GMP-Dependent Protein Kinase,G-Kinase,G-Kinases,Guanosine Cyclic 3',5'-Phosphate-Dependent Protein Kinase,Protein Kinase G,Cyclic GMP Dependent Protein Kinase,Cyclic GMP Dependent Protein Kinases,G Kinase,G Kinases,Guanosine Cyclic 3',5' Phosphate Dependent Protein Kinase,Guanosine Cyclic Monophosphate Dependent Protein Kinase,Guanosine Cyclic Monophosphate Dependent Protein Kinases,Kinase, cGMP-Dependent Protein,Kinases, cGMP-Dependent Protein,Protein Kinase, cGMP-Dependent,Protein Kinases, cGMP-Dependent,cGMP Dependent Protein Kinase,cGMP Dependent Protein Kinases

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