Activation of K+ channels and suppression of neuronal activity by secreted beta-amyloid-precursor protein

Nature. 1996 Jan 4;379(6560):74-8. doi: 10.1038/379074a0.


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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Action Potentials
  • Amyloid beta-Protein Precursor / metabolism
  • Amyloid beta-Protein Precursor / physiology*
  • Animals
  • Calcium / metabolism
  • Cell Line
  • Cells, Cultured
  • Cyclic GMP / analogs & derivatives
  • Cyclic GMP / metabolism
  • Egtazic Acid / analogs & derivatives
  • Egtazic Acid / pharmacology
  • Ethers, Cyclic / pharmacology
  • Hippocampus / cytology
  • Neural Inhibition
  • Neurons / physiology*
  • Nitroprusside / pharmacology
  • Okadaic Acid
  • Potassium Channels / drug effects
  • Potassium Channels / metabolism*
  • Rats


  • Amyloid beta-Protein Precursor
  • Ethers, Cyclic
  • Potassium Channels
  • 1,2-bis(2-aminophenoxy)ethane N,N,N',N'-tetraacetic acid acetoxymethyl ester
  • Nitroprusside
  • Okadaic Acid
  • Egtazic Acid
  • Cyclic GMP
  • Calcium