The Alzheimer's β-amyloid precursor protein (β-APP) is widely expressed in neural cells, and in neurons secreted forms of β-APP (sAPPs) are released from membrane-spanning holo-βAPP 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 β-APP regulates developmental and synaptic plasticity in the nervous system.
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