Direct Modulation of Calmodulin Targets by the Neuronal Calcium Sensor NCS-1

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 93; no. 17; pp. 9253 - 9258
• Main Authors: Schaad, Nicolas C., De Castro, Edouard, Nef, Serge, Hegi, Sarah, Hinrichsen, Robert, Martone, Maryann E., Ellisman, Mark H., Sikkink, Robert, Rusnak, Frank, Sygush, Jurgen, Nef, Patrick
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences of the United States of America 20.08.1996; National Acad Sciences; National Academy of Sciences
• Subjects: Animals; Biochemistry; Brain; Brain - cytology; Brain - drug effects; Brain - metabolism; Calcineurin; Calcium; Calcium - metabolism; Calcium-Binding Proteins - isolation & purification; Calcium-Binding Proteins - pharmacology; Calmodulin - deficiency; Calmodulin - metabolism; Calmodulin-Binding Proteins - drug effects; Calmodulin-Binding Proteins - metabolism; Cattle; Chickens; Crystals; Dose-Response Relationship, Drug; Enzyme Activation; Enzymes; Hippocampus - chemistry; Identity; Immunohistochemistry; In Vitro Techniques; Microinjections; Nervous system; Neuronal Calcium-Sensor Proteins; Neurons; Neurons - drug effects; Neurons - metabolism; Neuropeptides - isolation & purification; Neuropeptides - pharmacology; Nitric Oxide Synthase - drug effects; Nitric Oxide Synthase - metabolism; Paramecium - genetics; Paramecium - metabolism; Phosphatases; Phosphoprotein Phosphatases - drug effects; Phosphoprotein Phosphatases - metabolism; Phosphoric Diester Hydrolases - drug effects; Phosphoric Diester Hydrolases - metabolism; Rats; Recombinant Proteins - pharmacology; Sensors; Tissue Distribution
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.93.17.9253

Ca2+ and its ubiquitous intracellular receptor calmodulin (CaM) are required in the nervous system, among a host of cellular responses, for the modulation of several important enzymes and ion channels involved in synaptic efficacy and neuronal plasticity. Here, we report that CaM can be replaced by the neuronal calcium sensor NCS-1 both in vitro and in vivo. NCS-1 is a calcium binding protein with two Ca2+-binding domains that shares only 21% of homology with CaM. We observe that NCS-1 directly activates two Ca2+/CaM-dependent enzymes 3′:5′-cyclic nucleotide phosphodiesterase and protein phosphatase calcineurin). Co-activation of nitric oxide synthase by NCS-1 and CaM results in a higher activity than with CaM alone. Moreover, NCS-1 is coexpressed with calcineurin and nitric oxide synthase in several neuron populations. Finally, injections of NCS-1 into calmodulin-defective cam1 Paramecium partially restore wild-type behavioral responses. With this highly purified preparation of NCS-1, we have obtained crystals suitable for crystallographic structure studies. NCS-1, despite its very different structure, distribution, and Ca2+-binding affinity as compared with CaM, can substitute for or potentiate CaM functions. Therefore, NCS-1 represents a novel protein capable of mediating multiple Ca2+-signaling pathways in the nervous system.