Function: Couples NMDA-sensitive glutamate receptor signaling to the nucleus and triggers long-lasting changes in the cytoarchitecture of dendrites and spine synapse processes. Part of the cAMP response element-binding protein (CREB) shut-off signaling pathway. Stimulates outgrowth of olfactory axons and migration of gonadotropin-releasing hormone (GnRH) and luteinizing-hormone-releasing hormone (LHRH) neuronal cells. Ref.6
Subunit structure: Interacts with KPNA1; the interaction occurs in a calcium-independent manner after synaptic NMDA receptor stimulation and is required for nuclear import of NSMF but is competed by CABP1. Interacts (via the central NLS-containing motif region) with CABP1 (via EF-hands 1 and 2); the interaction occurs in a calcium-dependent manner after synaptic NMDA receptor stimulation and prevents the nuclear import of NSMF. Cannot be competed by calmodulin
By similarity.
Subcellular location: Nucleus. Nucleus envelope
By similarity. Nucleus membrane
By similarity. Nucleus matrix
By similarity. Cytoplasm. Cytoplasm › cell cortex
By similarity. Cytoplasm › cytoskeleton
By similarity. Cell membrane; Peripheral membrane protein. Cell projection › dendrite
By similarity. Cell junction › synapse
By similarity. Cell junction › synapse › synaptosome
By similarity. Cell junction › synapse › postsynaptic cell membrane › postsynaptic density
By similarity. Membrane
By similarity. Note: Found on the outside of the luteinizing-hormone-releasing hormone (LHRH) cell membrane and axons projecting from the olfactory pit and epithelium. Associates with transcriptionally active chromatin regions. Detected at the nuclear membranes of CA1 neurons. Cortical cytoskeleton. Localized in proximal apical dendrites. Colocalizes with CABP1 in dendrites and dendritic spines. Myristoylation is a prerequisite for extranuclear localization. Translocates from dendrites to the nucleus during NMDA receptor-dependent long-term potentiation (LTP) induction of synaptic transmission at Schaffer collateral/CA1 synapses of hippocampal primary neurons and in a importin-dependent manner
By similarity. Ref.6
Tissue specificity: Highly expressed in adult and fetal brain. Weakly expressed in heart, liver, spleen, testis, small intestine, skeletal muscle, peripheral white blood cells and kidney. Ref.1 Ref.6
Post-translational modification: Proteolytically processed after NMDA receptor activation. Cleaved in a calcium-dependent and calpain-sensitive manner. Calpain cleavage is essential for the translocation process from dendrites to the nucleus
By similarity.
Involvement in disease: Hypogonadotropic hypogonadism 9 with or without anosmia (HH9) [MIM:614838]: A disorder characterized by absent or incomplete sexual maturation by the age of 18 years, in conjunction with low levels of circulating gonadotropins and testosterone and no other abnormalities of the hypothalamic-pituitary axis. In some cases, it is associated with non-reproductive phenotypes, such as anosmia, cleft palate, and sensorineural hearing loss. Anosmia or hyposmia is related to the absence or hypoplasia of the olfactory bulbs and tracts. Hypogonadism is due to deficiency in gonadotropin-releasing hormone and probably results from a failure of embryonic migration of gonadotropin-releasing hormone-synthesizing neurons. In the presence of anosmia, idiopathic hypogonadotropic hypogonadism is referred to as Kallmann syndrome, whereas in the presence of a normal sense of smell, it has been termed normosmic idiopathic hypogonadotropic hypogonadism (nIHH).Note: The disease is caused by mutations affecting distinct genetic loci, including the gene represented in this entry. The genetics of hypogonadotropic hypogonadism involves various modes of transmission. Oligogenic inheritance has been reported in some patients carrying mutations in NSMF as well as in other HH-associated genes including FGFR1 (Ref.8). Ref.1 Ref.7 Ref.8
Miscellaneous: NSMF mRNAs expressed in the hippocampus exhibit a prominent dendritic localization which is mediated by a dendritic targeting element (DTE) residing in the 3'-untranslated region (3'UTR). Transport from dendrites to the nucleus is induced by NMDA receptor activation and results in a rapid stripping of synaptic contacts and a reduction of dendritic complexity
By similarity.
Sequence similarities: Belongs to the NSMF family.
Sequence caution: The sequence BAB55139.1 differs from that shown. Reason: Erroneous initiation. Translation N-terminally extended.The sequence CAI14577.1 differs from that shown. Reason: Erroneous gene model prediction. The sequence CAI14578.1 differs from that shown. Reason: Erroneous gene model prediction.
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