Purkinje cell dysfunction and delayed death in plasma membrane calcium ATPase 2-heterozygous mice.
Purkinje cell (PC) dysfunction or death has been implicated in a number of disorders including ataxia, autism and multiple sclerosis. Plasma membrane calcium ATPase 2 (PMCA2), an important calcium (Ca(2+)) extrusion pump that interacts with synaptic signaling complexes, is most abundantly expressed in PCs compared to other neurons. Using the PMCA2 heterozygous mouse as a model, we investigated whether a reduction in PMCA2 levels affects PC function. We focused on Ca(2+) signaling and the expression of glutamate receptors which play a key role in PC function including synaptic plasticity. We found that the amplitude of depolarization and 2-amino-3-(5-methyl-3-oxo-1,2-oxazol-4-yl)propanoic acid receptor (AMPAR)-mediated Ca(2+) transients are significantly higher in cultured PMCA2(+/-) PCs than in PMCA2(+/+) PCs. This is due to increased Ca(2+) influx, since P/Q type voltage-gated Ca(2+) channel (VGCC) expression was more pronounced in PCs and cerebella of PMCA2(+/-) mice and VGCC blockade prevented the elevation in amplitude. Neuronal nitric oxide synthase (nNOS) activity was higher in PMCA2(+/-) cerebella and inhibition of nNOS or the soluble guanylate cyclase (sGC)-cyclic guanosine monophosphate (cGMP) pathway, which mediates nitric oxide (NO) signaling, reduced the amplitude of Ca(2+) transients in PMCA2(+/-) PCs, in vitro. In addition, there was an age-dependent decrease in metabotropic glutamate receptor 1 (mGluR1) and AMPA receptor subunit GluR2/3 transcript and protein levels at 8 weeks of age. These changes were followed by PC loss in the 20-week-old PMCA2(+/-) mice. Our studies highlight the importance of PMCA2 in Ca(2+) signaling, glutamate receptor expression and survival of Purkinje cells.
Department of Neurological Surgery, University of Medicine and Dentistry of New Jersey, New Jersey Medical School, Newark, NJ, USA.
Amanda K
AK
Fakira
Lawrence D
LD
Gaspers
Andrew P
AP
Thomas
Hong
H
Li
Mohit R
MR
Jain
Stella
S
Elkabes
D000367:Age Factors; D000818:Animals; D002118:Calcium / Q000378:metabolism; D015220:Calcium Channels / Q000378:metabolism; D020013:Calcium Signaling; D016923:Cell Death; D002478:Cells, Cultured; D005786:Gene Expression Regulation; D006579:Heterozygote; D051379:Mice; D009569:Nitric Oxide / Q000378:metabolism; D019001:Nitric Oxide Synthase / Q000378:metabolism; D053499:Plasma Membrane Calcium-Transporting ATPases / Q000235:genetics* / Q000378:metabolism; D011689:Purkinje Cells / Q000166:cytology / Q000378:metabolism*; D018091:Receptors, AMPA / Q000235:genetics / Q000378:metabolism; D018094:Receptors, Metabotropic Glutamate / Q000378:metabolism; D014158:Transcription, Genetic
D015220:Calcium Channels; D018091:Receptors, AMPA; D018094:Receptors, Metabotropic Glutamate; C104077:metabotropic glutamate receptor type 1; D009569:Nitric Oxide; D019001:Nitric Oxide Synthase; D053499:Plasma Membrane Calcium-Transporting ATPases; C506959:Atp2b2 protein, mouse; D002118:Calcium