TY - JOUR
T1 - Restoration of TEA-induced calcium responses in fibroblasts from Alzheimer's disease patients by a PKC activator
AU - Bhagavan, Seetha
AU - Ibarreta, Dolores
AU - Ma, Dawei
AU - Kozikowski, Alan P.
AU - Etcheberrigaray, René
N1 - Funding Information:
We thank Dr. G. D. Brooker for his assistance in installing the calcium imaging system and C. D. Kerns and C. W. Jacob Jr. for their help with the cell culture. Supported partially by a DOD grant (S.B., R.E., and A.K.) and a starter grant from the Office of the Dean of Research and Graduate Education (R.E.). D.I. is on a Ministerio de Educación (Spain) fellowship.
PY - 1998/9
Y1 - 1998/9
N2 - Several alterations in fibroblasts of Alzheimer's disease (AD) patients have been described, including alterations in calcium regulation, protein kinase C (PKC), and potassium (K+) channels. Studies have also found reduced levels of the α isoform of PKC in brains and fibroblasts of AD patients. Since PKC is known to regulate ion channels, we studied K+ channel activity in fibroblasts from AD patients in the presence of (2S, 5S)-8-(1- decynyl)benzolactam (BL), a novel activator of PKC with improved selectivity for the α, β, and γ isoforms. We present evidence for restoration of normal K+ channel function, as measured by TEA-induced [Ca2+](i) elevations, due to activation of PKC by BL. Representative patch-clamp data further substantiate the effect of BL on restoration of 113pS K+ channel activity. Immunoblotting analyses using an α-isozyme-specific PKC antibody confirm that BL-treated fibroblasts of AD patients show increased PKC activation. The present study suggests that PKC activator-based restoration of K+ channels may offer another approach to the investigation of AD pathophysiology, which in turn could lead to the development of a useful model for AD therapeutics.
AB - Several alterations in fibroblasts of Alzheimer's disease (AD) patients have been described, including alterations in calcium regulation, protein kinase C (PKC), and potassium (K+) channels. Studies have also found reduced levels of the α isoform of PKC in brains and fibroblasts of AD patients. Since PKC is known to regulate ion channels, we studied K+ channel activity in fibroblasts from AD patients in the presence of (2S, 5S)-8-(1- decynyl)benzolactam (BL), a novel activator of PKC with improved selectivity for the α, β, and γ isoforms. We present evidence for restoration of normal K+ channel function, as measured by TEA-induced [Ca2+](i) elevations, due to activation of PKC by BL. Representative patch-clamp data further substantiate the effect of BL on restoration of 113pS K+ channel activity. Immunoblotting analyses using an α-isozyme-specific PKC antibody confirm that BL-treated fibroblasts of AD patients show increased PKC activation. The present study suggests that PKC activator-based restoration of K+ channels may offer another approach to the investigation of AD pathophysiology, which in turn could lead to the development of a useful model for AD therapeutics.
KW - Alzheimer's disease
KW - Calcium
KW - Fibroblast
KW - Protein kinase C
KW - TEA
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U2 - 10.1006/nbdi.1998.0195
DO - 10.1006/nbdi.1998.0195
M3 - Article
C2 - 9848089
AN - SCOPUS:0031797871
SN - 0969-9961
VL - 5
SP - 177
EP - 187
JO - Neurobiology of Disease
JF - Neurobiology of Disease
IS - 3
ER -