Gating, Regulation, and Structure in K_2P K⁺ Channels: In Varietate Concordia?

Abstract

1 channels with two pore domains in tandem associate as dimers to produce so-called background conductances that are regulated by a variety of stimuli. Whereas gating in K 2P channels has been poorly understood, recent developments have provided important clues regarding the gating mechanism for this family of proteins. Two modes of gating present in other K 1 channels have been considered. The first is the so-called activation gating that occurs by bundle crossing and the splaying apart of pore-lining helices commanding ion passage. The second mode involves a change in conformation at the selectivity filter (SF), which impedes ion flow at this narrow portion of the conduction pathway and accounts for extracellular pH modulation of several K 2P channels. Although some evidence supports the existence of an activation gate in K 2P channels, recent results suggest that perhaps all stimuli, even those sensed at a distant location in the protein, are also mediated by SF gating. Recently resolved crystal structures of K 2P channels in conductive and nonconductive conformations revealed that the nonconductive state is reached by blockade by a lipid acyl chain that gains access to the channel cavity through intramembrane fenestrations. Here we discuss whether this novel type of gating, proposed so far only for membrane tension gating, might mediate gating in response to other stimuli or whether SF gating is the only type of opening/closing mechanism present in K 2P channels.

Molecular determinants of chemical modulation of two‐pore domain potassium channels

“…However, the K2P channels are no longer considered merely “leakage” channels, but in fact have been demonstrated to play important regulatory roles in processes of high physiological and pathophysiological significance and are expressed in virtually all tissues (Renigunta et al., ). Past reviews have dealt with many aspects related to K2Ps such as their therapeutic potential (Es‐Salah‐Lamoureux, Steele, & Fedida, ; Mathie & Veale, ; Wiedmann et al., ), function (Niemeyer, Cid, Gonzalez, & Sepulveda, ; Renigunta et al., ; Schmidt et al., ), and pharmacology (Gada & Plant, ; Kim, ), revealing an ever‐expanding knowledge about their importance in living cells while presenting an increasing therapeutic interest as promising targets in cancer, pain, depression, and in diseases of the lung, heart, and kidney.…”

“…In the transition from the “up” state to the “down” state, the M4 helix moves laterally from its opposing M2 helix, allowing the side fenestrations to be opened. In this way, the inner pore can be tunneled to a direct interaction with membrane lipids, which may be linked to the gating process (Aryal et al., ; Niemeyer et al., ) and also allows the side fenestrations to potentially interact with chemical molecules (Figure c). K2Ps also exhibit a domain‐swapped chain connectivity (Niemeyer et al., ), which was not noticed in initial crystals and swaps the outer helices around the overall structure (Figure b,c).…”

“…In this way, the inner pore can be tunneled to a direct interaction with membrane lipids, which may be linked to the gating process (Aryal et al., ; Niemeyer et al., ) and also allows the side fenestrations to potentially interact with chemical molecules (Figure c). K2Ps also exhibit a domain‐swapped chain connectivity (Niemeyer et al., ), which was not noticed in initial crystals and swaps the outer helices around the overall structure (Figure b,c). Additionally, the M4 helix manifests a kink in TWIK‐1 (Miller & Long, ); this is not the case in TREK subfamily structures (Lolicato et al., ), where it resembles a long α‐helix slightly curved toward the membrane (Figure b,c).…”

“…The other common way of tuning K2P activity is by hydrophobic gating. Such gating is thought to rely on the side fenestrations’ movement, which may allow membrane lipids to directly block the pore under the SF, while recent evidences suggest how the pore‐facing neutral side chains hinder ion passage by electrostatic “dewetting” in some K2P family members (Aryal et al., ; Niemeyer et al., ).…”

A Latin American Perspective on Ion Channels

“…The present special issue broadcasts a series of minireviews provided by only a subset of the outstanding scientists working in Latin America. It includes the structure, function, and/or modulation of the transient receptor potential channel vanilloid 1 (Diaz-Franulic et al, 2016), K 1 channels (Moreno-Galindo et al, 2016;Niemeyer et al, 2016) and ligand-gated ion channels (Burgos et al, 2016;Calvo and Beltrán González, 2016;Corradi and Bouzat, 2016). The participation of ion channels in pathophysiology-like cell volume regulation (Pasantes-Morales, 2016), pancreatic b-cell function (Velasco et al, 2016), autophagy (Filippi-Chiela et al, 2016), and cancer (Morrone et al, 2016;Fernandez et a., 2016) is also highlighted.…”