Enhanced accumulation of Kir4.1 protein, but not mRNA, in a murine model of cuprizone-induced demyelination.
Two channel proteins, inwardly rectifying potassium channel 4.1 (Kir4.1) and water channel aquaporin-4 (AQP4), were recently identified as targets of an autoantibody response in patients with multiple sclerosis and neuromyelitis optica, respectively. In the present study, we examined the expression patterns of Kir4.1 and AQP4 in a mouse model of demyelination induced by cuprizone, a copper chelator. Demyelination was confirmed by immunohistochemistry using an anti-proteolipid protein antibody in various brain regions, including the corpus callosum, of cuprizone-fed mice. Activation of microglial and astroglial cells was also confirmed by immunohistochemistry, using an anti-ionized calcium binding adapter molecule and a glial fibrillary acidic protein antibody. Western blot analysis revealed the induction of Kir4.1 protein, but not AQP4, in the cortex of cuprizone-fed mice. Immunohistochemical analysis confirmed the Kir4.1 protein induction in microvessels of the cerebral cortex. Real-time polymerase chain reaction analysis revealed that mRNA levels of Kir4.1 and AQP4 in the cortex did not change during cuprizone administration. These findings suggest that enhanced accumulation of Kir4.1 protein in the brain with an inflammatory condition facilitates the autoantibody formation against Kir4.1 in patients with multiple sclerosis.
Department of Pharmaceutical Pharmacology, School of Clinical Pharmacy, College of Pharmaceutical Sciences, Matsuyama University, 4-2 Bunkyo-cho, Matsuyama 790-8578, Ehime, Japan. Electronic address: mnakajim@cc.matsuyama-u.ac.jp.
Mitsunari
M
Nakajima
Takuya
T
Kawamura
Ryuji
R
Tokui
Kohei
K
Furuta
Mami
M
Sugino
Masayuki
M
Nakanishi
Satoshi
S
Okuyama
Yoshiko
Y
Furukawa
D000818:Animals; D051401:Aquaporin 4 / Q000276:immunology / Q000378:metabolism; D001323:Autoantibodies / Q000378:metabolism; D001921:Brain / Q000276:immunology / Q000378:metabolism*; D003471:Cuprizone / Q000494:pharmacology; D003711:Demyelinating Diseases / Q000139:chemically induced; D005260:Female; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D007150:Immunohistochemistry / Q000379:methods; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009471:Neuromyelitis Optica / Q000276:immunology / Q000378:metabolism*; D024661:Potassium Channels, Inwardly Rectifying / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism*; D013116:Spinal Cord / Q000378:metabolism; D000098854:Kcnj10 Channel
D051401:Aquaporin 4; D001323:Autoantibodies; D005904:Glial Fibrillary Acidic Protein; D000098854:Kcnj10 Channel; D024661:Potassium Channels, Inwardly Rectifying; D012333:RNA, Messenger; D003471:Cuprizone
APP; AQP4; Alzheimer's precursor protein; Aquaporin-4; Astroglia; Autoantibody; CC; CNS; GFAP; Iba-1; Kir4.1; MS; Multiple sclerosis; NMO; Neuromyelitis optica; OPC; PBS(−); PLP; aquaporin-4; central nervous system; corpus callosum; glial fibrillary acidic protein; inwardly rectifying potassium channel 4.1; ionized calcium binding adapter molecule; magnesium and calcium-free phosphate buffered saline; multiple sclerosis; neuromyelitis optica; olig2; oligodendrocyte precursor cells; oligodendrocyte transcription factor 2; proteolipid protein