Regulation of neuronal KCNQ2 channel by Src: dual rearrangement of cytosolic termini underlies bidirectional gating regulation

Neuronal M-type K+ channels heteromers of KCNQ2 and KCNQ3 subunits found in cell bodies, dendrites and the axon initial segment, regulate firing properties of neurons, while presynaptic KCNQ2 homomeric channels directly regulate neurotransmitter release. Previously, we have described a mechanism for gating down-regulation of KCNQ2 homomeric channels by calmodulin and syntaxin1A. Here, we describe a novel mechanism for KCNQ2 channels gating regulation utilized by Src, a non-receptor tyrosine kinase, in which two concurrent distinct structural rearrangements of the cytosolic termini induce two opposing effects, up-regulation of single-channel open probability, mediated by an N-terminal tyrosine, and reduction in functional channels, mediated by a C-terminal tyrosine. In contrast, Src regulation of KCNQ3 homomeric channels, shown before to be mediated by corresponding tyrosines, involves N-terminal tyrosine-mediated down-regulation of the open probability, rather than up-regulation. We argue that the dual bidirectional regulation of KCNQ2 functionality by Src, mediated via two separate sites, renders it modifiable by cellular factors that may specifically interact with either one of the sites, bearing potential significance in the fine-tuning of neurotransmitters release at nerve terminals.