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Mechanically Induced Hyperpolarization Via K2P Background Potassium Channels

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International Journal of Molecular Sciences Review Negative Influence by the Force: Mechanically Induced Hyperpolarization via K2P Background Potassium Channels Miklós Lengyel ,Péter Enyedi and Gábor Czirják * Department of Physiology, Semmelweis University, P.O. Box 2, H-1428 Budapest, Hungary; [email protected] (M.L.); [email protected] (P.E.) * Correspondence: [email protected] Abstract: The two-pore domain K2P subunits form background (leak) potassium channels, which are characterized by constitutive, although not necessarily constant activity, at all membrane potential values. Among the fifteen pore-forming K2P subunits encoded by the KCNK genes, the three members of the TREK subfamily, TREK-1, TREK-2, and TRAAK are mechanosensitive ion channels. Mechanically induced opening of these channels generally results in outward K+ current under physiological conditions, with consequent hyperpolarization and inhibition of membrane potential- dependent cellular functions. In the past decade, great advances have been made in the investigation of the molecular determinants of mechanosensation, and members of the TREK subfamily have emerged among the best-understood examples of mammalian ion channels directly influenced by the tension of the phospholipid bilayer. In parallel, the crucial contribution of mechano-gated TREK channels to the regulation of membrane potential in several cell types has been reported. In this review, we summarize the general principles underlying the mechanical activation of K2P channels, and focus on the physiological roles of mechanically induced hyperpolarization. Citation: Lengyel, M.; Enyedi, P.; Keywords: mechanosensitive; potassium channel; membrane tension; stretch; KCNK2; KCNK4; Czirják, G. Negative Influence by KCNK10; TREK1; TREK2 the Force: Mechanically Induced Hyperpolarization via K2P Background Potassium Channels. Int. J. Mol. Sci. 2021, 22, 9062. https:// 1. Introduction doi.org/10.3390/ijms22169062 The two-pore domain (K2P) potassium channels are the molecular correlates of back- + Academic Editor: Rashid Giniatullin ground (leak) potassium currents, which mediate K transport through the plasma mem- brane, regulate the value of the membrane potential, and adjust cellular excitability [1]. Received: 29 July 2021 The different K2P channel types are characterized by similar membrane topology, molecular Accepted: 20 August 2021 architecture, and overall electrophysiological properties. The K2P channels have four trans- Published: 23 August 2021 membrane segments and two pore domains in a subunit (4TM/2P architecture, Figure1A) . As in the other families of potassium channels, the selectivity filter of K2P channels is Publisher’s Note: MDPI stays neutral constituted by the TVGYG-like signature sequences of four pore domains, accordingly, with regard to jurisdictional claims in assembled by the dimerization of two-pore domain subunits (Figure1B), and considered published maps and institutional affil- as the major location of channel gating [2–9]. iations. The first extracellular loop of K2P channels is longer than the second one; this first loop contains conserved α-helices to establish a cap structure, through which the extracel- lular ion pathway (EIP) provides access to the narrow outer end of the transmembrane pore (Figure1B,C) [12–14]. Close to the intracellular opening of the pore, below the selectivity filter, Copyright: © 2021 by the authors. a wide central cavity is formed by the diverging transmembrane helices (Figure1C) . This cavity, + Licensee MDPI, Basel, Switzerland. just like the middle part of the EIP, may often accommodate a K ion partially retaining its This article is an open access article hydration shell. The K+ ion in the central cavity may be stabilized by the electric dipole moment distributed under the terms and of the pore helices, whereas in the middle part of the EIP by negatively charged amino acid side conditions of the Creative Commons chains in some K2P channel types (such as TASK-3 or TREK-2) [12,13,15,16]. Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ 4.0/). Int. J. Mol. Sci. 2021, 22, 9062. https://doi.org/10.3390/ijms22169062 https://www.mdpi.com/journal/ijms Int.Int. J. J. Mol. Mol. Sci. Sci.2021 2021, 22, 22, 9062, x FOR PEER REVIEW 2 ofof 2728 FigureFigure 1. 1. Schematic overview of of the the structure structure of of K K2P2P backgroundbackground potassium potassium channels. channels. (A) (TheA) Thegen- eral transmembrane topology of K2P channels is 4TM/2P. Only one subunit of the dimer is shown. general transmembrane topology of K2P channels is 4TM/2P. Only one subunit of the dimer is The membrane is illustrated with two horizontal black lines, both the N- and C-terminus of the shown. The membrane is illustrated with two horizontal black lines, both the N- and C-terminus subunit (N and C) are intracellular (IC). The subunit contains two pore domains (P), which form of the subunit (N and C) are intracellular (IC). The subunit contains two pore domains (P), which reentrant loops on the extracellular (EC) side (indicated with red). A part of the long first extracel- formlular reentrantloop, N-terminal loops on to the the extracellular first pore domain (EC) side, constitutes (indicated thewith extracellular red). A partcap structure. of the long (B first) The extracellularpanoramic view loop, of N-terminal the crystal tostructure the first of pore TREK-2 domain, homodimer constitutes is shown the extracellular from the extracellular cap structure. side (B(PDB:) The panoramic4BW5). One view subunit of the is crystal orange structure (pore loops of TREK-2 are red) homodimer and the other is shown is blue, from and the extracellularthe α-helical sideregions (PDB: are 4BW5). illustrated One subunitas tubes. is The orange first (poretransmembrane loops are red) segment and the (T otherM1) is is followed blue, and by the theα -helicaltwo cap regionshelices are(C1 illustrated and C2). After as tubes. C2, the The first first pore transmembrane helix (P1) diagonally segment immerses (TM1) is followed into the transmembrane by the two cap helicesspace, (C1and andthe chain C2). After vertically C2, the returns first pore to the helix EC (P1)side diagonallyas the (TVGYG-like) immerses si intognature the transmembrane sequence of the + space,selectivity and thefilter chain (narrow vertically rectangle returns close to to the the EC K side binding as the sites, (TVGYG-like) illustrated with signature spheres). sequence The pore of helix and the signature sequence belong to the first pore domain, as illustrated in panel A. The amino the selectivity filter (narrow rectangle close to the K+ binding sites, illustrated with spheres). The pore acid chain continues as the (not entirely straight) TM2 and TM3 transmembrane helices, followed helix and the signature sequence belong to the first pore domain, as illustrated in panel A. The amino by the second pore domain, which includes the P2 pore helix and the other signature sequence ro- acidtated chain by approx. continues 90 degrees as the (not around entirely the straight) axis of the TM2 pore, and compared TM3 transmembrane to the first one. helices, Finally, followed the chain by thereturns second to porethe IC domain, side as whichthe TM4 includes transmembrane the P2 pore helix. helix Some and the coils other connecting signature the sequence helical elements rotated by(e.g., approx. between 90 degreesC2 and P1, around TM2 theand axis TM3) of theand pore,the long compared C-terminal to the tail first following one. Finally, TM4 are the missing chain returnsfrom the to crystal the IC sidestructure. as the The TM4 figure transmembrane was produced helix. by Some the Cn3D coils software connecting of theNCBI. helical (C) elementsThe extra- (e.g.,cellular between ion pathway C2 and P1, (EIP) TM2 below and TM3)the cap and structure the long connects C-terminal the tail EC following end of the TM4 transmembrane are missing from pore theto the crystal EC space structure. as a T-shaped The figure bi wasfurcation. produced The bynarrow the Cn3D selectivity software filter of region NCBI. of (C the) The transmembrane extracellular + ionpore pathway is illustrated (EIP) below as a series the cap of structurefour K binding connects sites the EC(purple end ofspheres). the transmembrane Below the selectivity pore to the filter, EC the pore widens as the central cavity. The TREK-2 homodimer is rotated by about a quarter turn, space as a T-shaped bifurcation. The narrow selectivity filter region of the transmembrane pore is compared to panel B, the cap helices of the two subunits almost overlap in the illustration. The EIP illustrated as a series of four K+ binding sites (purple spheres). Below the selectivity filter, the pore and central cavity are determined as the spaces accessible by a small sphere (radius 2.1 Å), but not widensby a large as the one central (radius cavity. 4.5 Å The for TREK-2the EIP and homodimer 8.1 Å for is the rotated central by cavity), about a by quarter using turn,PrinCCes compared [10] and to panelVMD B ,[11] the software. cap helices The of green the two spheres subunits are adjacent almost overlap to bulk influid. the illustration. The EIP and central cavity are determined as the spaces accessible by a small sphere (radius 2.1 Å), but not by a large one (radiusThe first 4.5 Å extracellular for the EIP and loop 8.1 Åof for K the2P channels central cavity), is longer by using than PrinCCes the second [10] andone; VMD this [first11] software.loop contains The green conserved spheres α are-helices adjacent to toestablish bulk fluid. a cap structure, through which the extracel- lular ion pathway (EIP) provides access to the narrow outer end of the transmembrane K channels have background (K+-selective leak) characteristics, their macroscopic pore (Figure2P 1B,C) [12–14]. Close to the intracellular opening of the pore, below the selec- current is much better approximated by the Goldman–Hodgkin–Katz (GHK) current equa- tivity filter, a wide central cavity is formed by the diverging transmembrane helices (Fig- tion than the current of the voltage-gated (K ) or inwardly rectifying (K ) channel types.
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