Regulation of the neuronal KCNQ2 channel by Src--a dual rearrangement of the cytosolic termini underlies bidirectional regulation of gating.
Neuronal M-type K(+) channels are heteromers of KCNQ2 and KCNQ3 subunits, and are found in cell bodies, dendrites and the axon initial segment, regulating the firing properties of neurons. By contrast, presynaptic KCNQ2 homomeric channels directly regulate neurotransmitter release. Previously, we have described a mechanism for gating downregulation of KCNQ2 homomeric channels by calmodulin and syntaxin1A. Here, we describe a new mechanism for regulation of KCNQ2 channel gating that is modulated by Src, a non-receptor tyrosine kinase. In this mechanism, two concurrent distinct structural rearrangements of the cytosolic termini induce two opposing effects: upregulation of the single-channel open probability, mediated by an N-terminal tyrosine, and reduction in functional channels, mediated by a C-terminal tyrosine. In contrast, Src-mediated regulation of KCNQ3 homomeric channels, shown previously to be achieved through the corresponding tyrosine residues, involves the N-terminal-tyrosine-mediated downregulation of the open probability, rather than an upregulation. We argue that the dual bidirectional regulation of KCNQ2 functionality by Src, mediated through two separate sites, means that KCNQ2 can be modified by cellular factors that might specifically interact with either one of the sites, with potential significance in the fine-tuning of neurotransmitters release at nerve terminals.
Department of Physiology and Pharmacology, Sackler School of Medicine, Tel-Aviv University, Ramat Aviv 69978, Israel.
Sivan
S
Siloni
Department of Physiology and Pharmacology, Sackler School of Medicine, Tel-Aviv University, Ramat Aviv 69978, Israel.
Dafna
D
Singer-Lahat
Department of Physiology and Pharmacology, Sackler School of Medicine, Tel-Aviv University, Ramat Aviv 69978, Israel.
Moad
M
Esa
Department of Physiology and Pharmacology, Sackler School of Medicine, Tel-Aviv University, Ramat Aviv 69978, Israel.
Vlad
V
Tsemakhovich
Department of Physiology and Pharmacology, Sackler School of Medicine, Tel-Aviv University, Ramat Aviv 69978, Israel.
Dodo
D
Chikvashvili
Department of Physiology and Pharmacology, Sackler School of Medicine, Tel-Aviv University, Ramat Aviv 69978, Israel ilotan@post.tau.ac.il.
Ilana
I
Lotan
D000818:Animals; D001369:Axons / Q000502:physiology; D002147:Calmodulin / Q000378:metabolism; D003600:Cytosol / Q000502:physiology; D006801:Humans; D015640:Ion Channel Gating; D051658:KCNQ2 Potassium Channel / Q000502:physiology*; D009474:Neurons / Q000502:physiology*; D011994:Recombinant Proteins / Q000378:metabolism; D009435:Synaptic Transmission; D014982:Xenopus laevis; D019061:src-Family Kinases / Q000502:physiology
D002147:Calmodulin; D051658:KCNQ2 Potassium Channel; D011994:Recombinant Proteins; D019061:src-Family Kinases
FRET; Gating; KCNQ2; Open probability; Src