Molecular mechanisms underlying membrane-potential-mediated regulation of neuronal K2P2.1 channels.
The activity of background K(2P) channels adjusts the resting membrane potential to enable plasticity of excitable cells. Here we have studied the regulation of neuronal K(2P)2.1 (KCNK2, TREK-1) channel activity by resting membrane potential. When heterologously expressed, K(2P)2.1 currents gradually increased at hyperpolarizing potentials and declined at depolarizing potentials, with a midpoint potential of -60 mV. As K(2P) channels are not equipped with an integral voltage sensor, we sought extrinsic cellular components that could convert changes in the membrane electrical field to cellular activity that would indirectly modify K(2P)2.1 currents. We propose that membrane depolarization activated the Gq protein-coupled receptor pathway, in the apparent absence of ligand, resulting in phosphatidylinositol-4,5-bisphosphate (PIP(2)) depletion through the action of phospholipase C. Our results suggest a novel mechanism in which an indirect pathway confers membrane potential regulation onto channels that are not intrinsically voltage sensitive to enhance regulation of neuronal excitability levels.
Segal-Hayoun
Yifat
Y
Department of Life Sciences and the Zlotowski Center for Neuroscience, Ben-Gurion University of the Negev, Beer-Sheva 84105, Israel.
Cohen
Asi
A
Zilberberg
Noam
N
D000595:Amino Acid Sequence; D000818:Animals; D004791:Enzyme Inhibitors / Q000378:metabolism; D043802:GTP-Binding Protein alpha Subunits, Gq-G11 / Q000378:metabolism; D020868:Gene Silencing; D006801:Humans; D015640:Ion Channel Gating / Q000502:physiology; D008564:Membrane Potentials / Q000502:physiology*; D008969:Molecular Sequence Data; D009474:Neurons / Q000166:cytology / Q000378:metabolism*; D009865:Oocytes / Q000166:cytology / Q000502:physiology; D018408:Patch-Clamp Techniques; D019269:Phosphatidylinositol 4,5-Diphosphate / Q000378:metabolism; D024683:Potassium Channels, Tandem Pore Domain / Q000235:genetics / Q000378:metabolism*; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism; D016415:Sequence Alignment; D010738:Type C Phospholipases / Q000378:metabolism; D014982:Xenopus laevis
D004791:Enzyme Inhibitors; D019269:Phosphatidylinositol 4,5-Diphosphate; D024683:Potassium Channels, Tandem Pore Domain; D043562:Receptors, G-Protein-Coupled; C103742:potassium channel protein TREK-1; D010738:Type C Phospholipases; D043802:GTP-Binding Protein alpha Subunits, Gq-G11