Oxidation of K+ Channels Leads to Progressive Decline in Sensory Function during Ageing

Abstract

Reactive oxygen species (ROS) play an important role in the progressive neuronal function loss that is part of both the normal ageing process and neurodegenerative disease. A central question is whether voltage-gated K+ (Kv) channels, which are key regulators of neuronal excitability, are physiological targets of ROS and whether these interactions have a role in the mechanisms underlying age-related neurodegeneration. Here, we show that oxidation of K+ channel KVS-1 during ageing causes sensory function loss in Caenorhabditis elegans, and that protection of this channel from oxidation preserves neuronal function.Thus, chemotaxis to biotin and lysine, a function controlled by KVS-1, was significantly impaired (70%) in normal or wild-type young worms exposed to chloramine-T (CHT) or hydrogen peroxide (H2O2), but only moderately affected (35%) in worms harboring an oxidation-reduction (redox)-resistant KVS-1 mutant (C113S). In ageing C113S worms, the effects of free radical accumulation were significantly attenuated (40% loss-of-function) compared to wild-type (75%). Electrophysiological analyses showed that both ROS accumulation during ageing, and acute exposure to oxidizing agents, acted primarily to modify native KVS-1 channels expressed in the ASER neuron (which mediates chemotaxis) and as a consequence altered the excitability of neurons harboring wild-type but not C113S KVS-1. Together, these findings establish a pivotal role for ROS-mediated oxidation of voltage-gated K+ channels in sensorial decline during ageing.