Activation of K+ channels and suppression of neuronal activity by secreted beta-amyloid-precursor protein.
The Alzheimer's beta-amyloid precursor protein (beta-APP) is widely expressed in neural cells, and in neurons secreted forms of beta-APP (sAPPs) are released from membrane-spanning holo-beta APP in an activity-dependent manner. Secreted APPs can modulate neurite outgrowth, synaptogenesis, synaptic plasticity and cell survival; a signal transduction mechanism of sAPPs may involve modulation of intracellular calcium levels ([Ca2+]i). Here we use whole-cell perforated patch and single-channel patch-clamp analysis of hippocampal neurons to demonstrate that sAPPs suppress action potentials and hyperpolarize neurons by activating high-conductance, charybdotoxin-sensitive K+ channels. Activation of K+ channels by sAPPs was mimicked by a cyclic GMP analogue and sodium nitroprusside and blocked by an antagonist of cGMP-dependent kinase and a phosphatase inhibitor, suggesting that the effect is mediated by cGMP and protein dephosphorylation. Calcium imaging studies indicate that activation of K+ channels mediates the ability of sAPPs to decrease [Ca2+]i. Modulation of neuronal excitability may be a major mechanism by which beta-APP regulates developmental and synaptic plasticity in the nervous system.
Sanders-Brown Research Center on Aging, University of Kentucky, Lexington 40536, USA.
K
K
Furukawa
S W
SW
Barger
E M
EM
Blalock
M P
MP
Mattson
D000200:Action Potentials; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism / Q000502:physiology*; D000818:Animals; D002118:Calcium / Q000378:metabolism; D002460:Cell Line; D002478:Cells, Cultured; D006152:Cyclic GMP / Q000031:analogs & derivatives / Q000378:metabolism; D004533:Egtazic Acid / Q000031:analogs & derivatives / Q000494:pharmacology; D004988:Ethers, Cyclic / Q000494:pharmacology; D006624:Hippocampus / Q000166:cytology; D009433:Neural Inhibition; D009474:Neurons / Q000502:physiology*; D009599:Nitroprusside / Q000494:pharmacology; D019319:Okadaic Acid; D015221:Potassium Channels / Q000187:drug effects / Q000378:metabolism*; D051381:Rats
D016564:Amyloid beta-Protein Precursor; D004988:Ethers, Cyclic; D015221:Potassium Channels; C070379:1,2-bis(2-aminophenoxy)ethane N,N,N',N'-tetraacetic acid acetoxymethyl ester; D009599:Nitroprusside; D019319:Okadaic Acid; D004533:Egtazic Acid; D006152:Cyclic GMP; D002118:Calcium