Calcium- and PTK-dependent suppression of macroscopic homomeric Kv1.1, Kv1.2, and heteromeric Kv1.1/1.2 currents by Aβ(1-42) peptide: Implications for Alzheimer’s disease

The roles of Aβ in Alzheimer’s disease pathogenesis include disruption of Ca2+ homeostasis, synaptic communication, and synaptic/neuronal plasticity underlying memory. How these abnormalities arise is incompletely understood. We have focused on the potential involvement of voltage-gated potassium channels (VGKCs) in these processes. VGKCs are activated by action potentials and regulate Ca2+ influx; inhibition of VGKCs can lead to synapto-/neuro-toxicity. In brain, Kv1.x family members are expressed as homotetramers or select heterotetramers (e.g., Kv1.1/Kv1.2 channels). We’ve previously shown that Aβ peptides rapidly suppress homomeric Kv1.1 activity in Xenopus oocytes: ∼50% suppression of Kv1.1 current within 30 m. Here we asked: 1) if Aβ(1-42) suppression is specific to Kv1.1 homomers, or also affects other Kv1.x family members (viz., homomeric Kv1.2 and 1.1/1.2 heteromers), 2) the extent to which suppression is Ca2+-dependent, 3) whether suppression is dependent on endogenous PTK activity. Oocytes were injected with Kv1.2 cRNA for homomeric expression. Heteromeric expression was evaluated by co-injection of Kv1.1 and 1.2 cRNAs. The acute effects of bath application of 1 μM Aβ(1-42) on macroscopic currents from homomeric Kv1.1, 1.2, and heteromeric 1.1/1.2 channels were measured using TEVC. As seen previously for Kv1.1 channels, Aβ suppressed Kv1.2 and heteromeric 1.1/1.2 channels by ∼45% and ∼46% in 30 m, respectively. BAPTA-AM (1 μM) reduced Aβ-suppression of 1.1, 1.2, and 1.1/1.2 currents by ∼50%, ∼60% and 100%, respectively. Suppressions were also greatly reduced by 50 μM cyclosporine A (CsA, a PP2B inhibitor) [∼50%, 100%, and 100%, respectively] and by the broad spectrum PTK inhibitor genistein (100 μM) (∼100% for all channel types). Our results implicate the involvement of intracellular Ca2+ and associated Ca2+-dependent enzymes (e.g., PP2B), as well as endogenous PTKs, in Aβ-suppressions of Kv1.x channels.