The Nuclear Localization of CAPON in Hippocampus and Cerebral Cortex Neurons after Lipopolysaccharide Stimulation

Abstract

Objective: In the brain, nitric oxide (NO) is a retrograde signalling molecule that transfers information from post- to pre-synaptic nerve endings. NO has been shown to be an important inflammatory mediator responding to lipopolysaccharide (LPS). It has been stated that the constitutive NO synthase isoforms (nNOS and eNOS) may also contribute to the inflammation. CAPON, a nNOS regulator, helps regulate nNOS stability, localization and possibly expression during synapse formation as well as muscle re-innervation. Recently, it has been reported that CAPON is associated with psychiatric illness. So we speculated that the CAPON expression-induced physiological changes may be mediated by modifications of NOS-NO signalling pathways. But little is known about the role of CAPON during the inflammation in the central nervous system, so we investigated the expression of CAPON in the brain treated with LPS. Methods and Results: Real-time PCR and Western blot showed that the expression of CAPON increased at mRNA and protein levels in the brain after LPS stimulation. Immunocytochemistry staining revealed that CAPON localized in the nuclei of neurons in the brain after peritoneal injection with LPS in vivo. The same phenomenon was also shown in primary cultured neurons in vitro incubated with LPS for 36 h. In addition, we found that CAPON had a colocalization with phosphorylated nNOS Ser847 but not with nNOS in hippocampus and cerebral cortex by double immunofluorescence. Conclusion: CAPON localized in the nuclei of neurons in hippocampus and cerebral cortex after LPS treatment. Because CAPON competed with PSD-95 for binding nNOS in neurons and nNOS was activated to produce NO through the NMDA- NMDAR pathway, we hypothesized that CAPON might play a proactive role in the process of inflammation by transferring from cytoplasm to the nucleus and through the NMDA-nNOS signal pathway. Further studies are required to clarify the mechanism of the nuclear localization of CAPON and the possible relationship with nNOS/NO signalling.

Tau binding protein CAPON induces tau aggregation and neurodegeneration

“…We next examined the involvement of neuroinflammation. Shao et al 20 reported that lipopolysaccharide (LPS) stimulation induces CAPON expression, and Cheng et al 21 proposed that CAPON increases after spinal cord injury. Therefore, neuroinflammation could also be involved in the elevation of CAPON expression under amyloid pathology.…”

CAPON Modulates Neuronal Calcium Handling and Cardiac Sympathetic Neurotransmission During Dysautonomia in Hypertension

“…29 It has been implicated in neuronal pathogenesis, including peripheral nerve regeneration, 28 neuron loss and survival, 29 schizophrenia, 30 pain, 29 and inflammation. 26 Here, we observed significant CAPON expression in both WKY and SHR stellate neurons; however, levels were significantly reduced in prehypertensive SHR neurons. Interestingly, CAPON is also present in choline acetyltransferase–positive intracardiac neurons (C.-J.…”

“…CAPON, a highly conserved protein, was first identified in rat brain neurons 26 as a binding protein for nNOS. 13 CAPON has been further discovered to be localized in ventricular myocytes, 10 rat neural tissues including the facial nerve, 27 sciatic nerve, 28,29 dorsal root ganglion, and lumbar spinal cord.…”

“…What is the cellular link to impaired intracellular Ca 2+ handling and is it related oxidative stress as some have suggested?. 20,26…”

The Hippo component YAP localizes in the nucleus of human papilloma virus positive oropharyngeal squamous cell carcinoma

“…Whether these interactions with YAP are related to the distinct subcellular localizations of the different NOS1AP isoforms remains to be determined. Interestingly, in neurons endogenous NOS1APa has been reported in the nucleus where non-phosphorylated YAP is found [ 39 ]. However, stable expression of NOS1APa is membrane localized in epithelial cell lines, and co-distributes with cytoplasmic YAP [ 23 ].…”