DIRECT MODULATION OF CALMODULIN TARGETS BY THE NEURONAL CALCIUM SENSOR NCS-1

Ca2+ and its ubiquitous intracellular receptor calmodulin (CaM) are re quired 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 an d in vivo, NCS-1 is a calcium binding protein with two Ca2+-binding do mains that shares only 21% of homology with CaM, We observe that NCS-1 directly activates two Ca2+/CaM-dependent enzymes (3':5'-cyclic nucle otide phosphodiesterase and protein phosphatase calcineurin). Coactiva tion of nitric oxide synthase by NCS-1 and CaM results in a higher act ivity than with CaM alone, Moreover, NCS-1 is coexpressed with calcine urin and nitric oxide synthase in several neuron populations, Finally, injections of NCS-1 into calmodulin-defective cam(1) Paramecium parti ally restore wild-type behavioral responses, With this highly purified preparation of NCS-1, we have obtained crystals suitable for crystall ographic structure studies, NCS-1, despite its very different structur e, distribution, and Ca2+-binding affinity as compared with CaM, can s ubstitute for or potentiate CaM functions, Therefore, NCS-1 represents a novel protein capable of mediating multiple Ca2+-signaling pathways in the nervous system.