The secreted form of the Alzheimer's beta-amyloid precursor protein stimulates a membrane-associated guanylate cyclase.
We previously demonstrated that secreted forms of the Alzheimer's beta-amyloid precursor protein (sAPP) elevate cyclic GMP (cGMP) in primary neuronal cultures and that this effect is responsible for the modulation of neuronal calcium homoeostasis by sAPP. We have investigated further the mechanism by which sAPP elevates cGMP. Inhibition of the formation of nitric oxide or carbon monoxide did not affect the ability of sAPP to lower rapidly intraneuronal calcium levels or elevate cGMP, suggesting that sAPP does not activate a soluble (cytosolic) guanylate cyclase. A dose-dependent stimulation of cGMP formation by sAPP was observed in brain membrane preparations. The stimulation was also dependent on the presence of ATP. These data suggest that sAPP activates a membrane-associated guanylate cyclase, perhaps similar to those present in the receptors for the natriuretic peptides and sperm motility factors.
Barger
S W
SW
Sanders-Brown Center on Aging, University of Kentucky, Lexington 40536-0230, USA.
Mattson
M P
MP
D000255:Adenosine Triphosphate / Q000494:pharmacology; D000544:Alzheimer Disease; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism* / Q000494:pharmacology*; D000818:Animals; D002118:Calcium / Q000378:metabolism; D002462:Cell Membrane / Q000201:enzymology*; D002478:Cells, Cultured; D006152:Cyclic GMP / Q000378:metabolism; D004622:Embryo, Mammalian; D004789:Enzyme Activation / Q000187:drug effects; D006162:Guanylate Cyclase / Q000378:metabolism*; D006624:Hippocampus / Q000201:enzymology; D009474:Neurons / Q000201:enzymology*; D051381:Rats; D017207:Rats, Sprague-Dawley
D016564:Amyloid beta-Protein Precursor; D000255:Adenosine Triphosphate; D006162:Guanylate Cyclase; D006152:Cyclic GMP; D002118:Calcium