Oxidation of KCNB1 K(+) channels in central nervous system and beyond

Abstract

KCNB1, a voltage-gated potassium (K(+)) channel that conducts a major delayed rectifier current in the brain, pancreas and cardiovascular system is a key player in apoptotic programs associated with oxidative stress. As a result, this protein represents a bona fide drug target for limiting the toxic effects of oxygen radicals. Until recently the consensus view was that reactive oxygen species trigger a pro-apoptotic surge in KCNB1 current via phosphorylation and SNARE-dependent incorporation of KCNB1 channels into the plasma membrane. However, new evidence shows that KCNB1 can be modified by oxidants and that oxidized KCNB1 channels can directly activate pro-apoptotic signaling pathways. Hence, a more articulated picture of the pro-apoptotic role of KCNB1 is emerging in which the protein induces cell's death through distinct molecular mechanisms and activation of multiple pathways. In this review article we discuss the diverse functional, toxic and protective roles that KCNB1 channels play in the major organs where they are expressed.

Keywords: Aging; Alzheimer’s disease; Apoptosis; Kv2.1; Reactive oxygen species.

Figure 1

A two-step model for the pro-apoptotic actions of KCNB1. Upon exposure to oxidants, KCNB1 oligomers are formed. They accumulate in the plasma membrane thereby perturbing the organization of lipid rafts. This results in activation of an apoptotic stimulus mediated by c-Src and downstream, JNK kinases. As result of activation of c-Src and JNK kinases and in part of NADPH-oxidase (Xilong Wu, private communication) which is localized in the plasma membrane, ROS levels increase in the cell. ROS induce a raise in cytosolic Ca²⁺ and Zn²⁺ that initiate a phosphorylation-mediated surge of KCNB1 channels that further drives apoptosis. The signaling pathway activated by Zn²⁺ proceeds through activation of p38 by ASK-1 and independently, of c-Src tyrosine kinases (Zn²⁺ inhibits the activity of the tyrosine phosphatase PTP epsilon) which phosphorylate KCNB1 at S800 and Y124 thereby allowing interaction with SNARE family protein syntaxin. The Ca²⁺ signaling pathway results in activation of CaMKII kinase which in turn acts to modulate the interaction of KCNB1 with syntaxin. It is not known whether Src and p38 phosphorylation directly act to increase KCNB1 current. ROS: Reactive oxygen species.