Amyloid beta peptide 1-40 stimulates the Na+/Ca2+ exchange activity of SNCX.
The Na+/Ca2+ exchangers, RNCX and SNCX, were cloned from mesangial cells of salt sensitive and salt resistant Dahl/Rapp rats, respectively, and differ at amino acid 218 (RNCXi/SNCXf) and in the exons expressed at the alternative splice site (RNCXB, D/SNCXB, D, F). These isoforms are also expressed in myocytes, neurons, and astrocytes where they maintain cytosolic calcium homeostasis. We demonstrated that cells expressing SNCX were more susceptible to oxidative stress than cells expressing RNCX. Others demonstrated that amyloid beta peptide (Abeta) augments the adverse effects of oxidative stress on calcium homeostasis. Therefore, we sought to assess the effect of Abeta 1-40 on the abilities of OK-PTH cells stably expressing RNCX and SNCX and human glioma cells, SKMG1, to regulate cytosolic calcium homeostasis. Our studies showed that Abeta 1-40 (1 microM) did not affect RNCX activity, as assessed by changes in [Ca2+]i (Delta[Ca2+]i, 260+/-10 nM to 267+/-8 nM), while stimulating exchange activity 2.4 and 3 fold in cells expressing SNCX (100+/-8 to 244+/-12 nM) and in SKMG1 cells (90+/-11 nM to 270+/-18 nM), respectively. Our results also showed that Abeta 1-40, while not affecting the rate of Mn2+ influx in cells expressing RNCX, stimulated the rate of Mn2+ influx 2.8 and 2.9 fold in cells expressing SNCX and in SKMG1 cells. Thus, our studies demonstrate that Abeta-induced cytosolic calcium increase is mediated through certain isoforms of the Na+/Ca2+ exchanger and reveals a possible mechanism by which Abeta 1-40 can alter cytosolic calcium homeostasis.
Unlap
Menjor Tino
MT
Nephrology Research and Training Center, Departments of Medicine and Physiology, Division of Nephrology, University of Alabama at Birmingham, Birmingham, AL 35294, USA. unlap@uab.edu
Williams
Corey
C
Morin
Darryl
D
Siroky
Brian
B
Fintha
Attila
A
Fuson
Amanda
A
Dodgen
Layla
L
Kovacs
Gergely
G
Komlosi
Peter
P
Ferguson
William
W
Bell
Phillip Darwin
PD
D016229:Amyloid beta-Peptides / Q000494:pharmacology*; D000818:Animals; D002118:Calcium / Q000378:metabolism; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D006706:Homeostasis / Q000187:drug effects; D006801:Humans; D007425:Intracellular Membranes / Q000378:metabolism; D008345:Manganese / Q000378:metabolism; D009893:Opossums; D009994:Osmolar Concentration; D018384:Oxidative Stress / Q000187:drug effects; D010446:Peptide Fragments / Q000494:pharmacology*; D051381:Rats; D020303:Rats, Inbred Dahl; D019831:Sodium-Calcium Exchanger / Q000378:metabolism*
D016229:Amyloid beta-Peptides; D010446:Peptide Fragments; D019831:Sodium-Calcium Exchanger; C078592:amyloid beta-protein (1-40); D008345:Manganese; D002118:Calcium