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The mechanisms underlying neuronal pathology and death in the spinal cord (SC) during inflammation remain elusive. We previously showed the important role of plasma membrane calcium ATPases (PMCAs) in the survival of SC neurons, in vitro. We also postulated that a decrease in PMCA2 expression could cause neuronal death during experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis. The current studies were undertaken to define the specific contribution of PMCA2 to degeneration of SC neurons, the effectors downstream to PMCA2 mediating neuronal death and the triggers that reduce PMCA2 expression. We report that knockdown of PMCA2 in SC neurons decreases collapsin response mediator protein 1 (CRMP1) levels. This is followed by cell death. Silencing of CRMP1 expression also leads to neuronal loss. Kainic acid reduces both PMCA2 and CRMP1 levels and induces neuronal death. Administration of an α-amino-3-hydroxyl-5-methyl-4-isoxazole-propionate (AMPA)/kainate receptor antagonist, at onset or peak of EAE, restores the decreased PMCA2 and CRMP1 levels to control values and ameliorates clinical deficits. Thus, our data link the reduction in PMCA2 expression with perturbations in the expression of CRMP1 and the ensuing death of SC neurons. This represents an additional mechanism underlying AMPA/kainate receptor-mediated excitotoxicity with relevance to neurodegeneration in EAE.

Plasma membrane calcium ATPase 2 (PMCA2) is a calcium pump that plays important roles in neuronal function. Although it is expressed in pain-associated regions of the CNS, including in the dorsal horn (DH), its contribution to pain remains undefined. The present study assessed the role of PMCA2 in pain responsiveness and the link between PMCA2 and glutamate receptors, GABA receptors (GABARs), and glutamate transporters that have been implicated in pain processing in the DH of adult female and male PMCA2 and PMCA2 mice. Behavioral assays evaluated mechanical and thermal pain responsiveness. Mechanical sensitivity was significantly increased by 52% and heat sensitivity was reduced by 29% in female, but not male, PMCA2 mice compared with PMCA2 controls. There were female-specific changes in metabotropic glutamate receptor 1, NMDA receptor 2A, α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor subunit GluR1, GABAR1, and GABAR2 levels, whereas metabotropic glutamate receptor 5, NMDA receptor 2B, GluR2, and GABARα2 levels were not altered. Glutamate aspartate transporter levels were higher and glial glutamate transporter 1 levels were lower in the DH of female, but not male, PMCA2 mice. These findings indicate a novel role for PMCA2 in modality- and sex-dependent pain responsiveness. Female-specific molecular changes potentially account for the altered pain responses.-Khariv, V., Ni, L., Ratnayake, A., Sampath, S., Lutz, B. M., Tao, X.-X., Heary, R. F., Elkabes, S. Impaired sensitivity to pain stimuli in plasma membrane calcium ATPase 2 (PMCA2) heterozygous mice: a possible modality- and sex-specific role for PMCA2 in nociception.

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