Focus Issue: Ion Channels: Opening the Gateless Gate

"When one passes through this gateless gate, he walks freely between heaven and earth." The Wu-men kuan (The Mumonkan, The Gateless Gate) ([1][1]) Channels, receptors, and carrier proteins in the plasma membrane comprise the initial springboard for communication between the external environment and the cell interior. Ion channels, which exploit the differences in electrolyte composition between the internal and external cellular milieu to transmit electrical and chemical signals, provide the most rapid and perhaps the most direct means of information transfer across the cell membrane. A host of channels has evolved that show selective permeability to different ionic species and that respond to various input modalities. Perhaps the most familiar of these are the sodium and potassium channels that underlie the propagated action potential of many excitable cells. These channels are voltage-gated: They change conformation and become permeable to ions in response to changes in the potential difference across the cell membrane. The ensuing ionic fluxes lead to the changes in membrane potential that allow the action potential to regenerate itself and propagate down an axon or through a muscle fiber. Some excitable cells exhibit persistent depolarizing currents and are spontaneously active. The firing of such cells can be modulated--or the firing of quiescent cells stimulated--by input from mechanically gated channels that open in response to deformation of the cell membrane or from ligand-gated channels, such as those that open in response to the binding of neurotransmitter. Some channels are indirectly gated--or otherwise modulated--in response to the activation of various intracellular second messenger pathways. This week's Science 's STKE focuses on ion channels: in particular, on the molecular mechanisms that underlie channel gating. In a Review on voltage-gated potassium channels, Armstrong describes the structural basis for ion selectivity, rapid conduction, and voltage-dependent activation and inactivation. Armstrong paints a vivid picture of potassium channel structure and function and of how early views of voltage-dependent channel function have been modified based on information obtained from biophysical analyses and through both ion channel cloning and the determination of the crystal structure of potassium channels. Focusing on the nicotinic acetylcholine receptor as a prototype of the pentameric family of ligand-gated ion channels, the Review by Auerbach explores the transition state between the closed and the open conformations of this protein. Experiments measuring changes in the rate constants of channel opening and closing following perturbations to individual residues suggest that gating occurs more or less as a reversible wave of conformational changes that propagates between the neurotransmitter-binding site and the membrane domain rather than an instantaneous all-or-none switch in protein conformation. An accompanying animation depicts a speculative view of acetylcholine receptor gating. The Perspective by Chen concerns the relationship between ion permeation and fast gating in ClC chloride channels. In this class of channels, one mechanism by which fast gating is coupled to chloride permeation appears to depend upon competition between permeating chloride ions and a carboxyl group on a glutamate residue that acts as a gate by blocking the channel pore. In this model, chloride ions compete with the negatively charged carboxyl group for an anion-binding site, helping explain the effect of intracellular chloride on channel gating. The STKE Archives contain many other articles pertinent to ion channels. The Protocol by Zheng and Zagotta describes patch-clamp fluorometry recording, a technique whereby structural changes in ion channels can be monitored simultaneously with changes in functional state. Conformational changes are reflected in changes in the emission of fluorophores attached to cysteines introduced through mutagenesis, whereas ionic currents can be measured through patch-clamp analysis. A Review by Montell highlights the TRP (transient receptor potential) superfamily, a group of relatively nonselective cation channels that are permeable to calcium and activated through pathways involving phospholipase C. Bonilla and Cunningham focus on TRP homologs in yeast and compare them to voltage-gated yeast calcium channels. Like many proteins involved in cell signaling, ion channels are subject to modulation by second messenger pathways, and many articles in the archives concern the pathways through which channels are regulated. Hilgemann et al . review the complexities inherent in the regulation of many classes of channels--including some TRP channels--by phosphatidylinositol-4,5-bisphosphate. The Perspective by Tasker discusses the coregulation of the chloride-permeable γ-aminobutyric acid (GABA) type A receptor and of voltage-dependent calcium channels by neurosteroids and phosphorylation. Trimmer describes the regulation of voltage-dependent calcium channel expression through the influence of a small guanosine triphosphatase on auxiliary subunit trafficking. Robinson and Messerli describe how ion fluxes contribute to pollen tube extension in plants. Hitting a more structural note, a Perspective by MacFarlane and Levitan highlights the role of leucine zipper motifs in ion channels and associated adaptor proteins in recruiting kinases and phosphatases into macromolecular complexes with various ion channels. Fury et al . discuss how alternative splicing in BK channels (calcium-sensitive, voltage-dependent potassium channels) can regulate their susceptibility to activation by different kinases. A Perspective by O' Donovan and Darnell extends this theme by discussing the regulation of neuronal ion channel splicing by neuronal activity, through depolarization and the subsequent influx of calcium. Fozzard and Kyle bring the issue of posttranslational modification of ion channels squarely into the medical realm by discussing the possible role of defects in ion channel glycosylation in contributing to cardiac arrhythmias. Action potentials, synaptic potentials, and mechanically gated receptor potentials are all electrical signals: Information is conveyed by transient changes in the potential difference across the cell membrane that stimulate conformational changes in voltage-gated channels. Ions traversing the cell membrane can also act to modulate channel activity and other cellular targets. In regions with restricted extracellular space, for example, the build-up of extracellular potassium can produce a sustained low-level depolarization, which can increase the percentage of inactivated sodium channels and influence the firing of neurons in that area. As already indicated, calcium fluxes can initiate various cascades that lead to the modulation of ion channel function. Calcium also plays a key role as a second messenger in coupling excitation to secretion, contraction, and transcription, as well as influencing numerous cellular functions. The Perspective by Dolmetsch describes the role of local increases in calcium near the mouths of calcium channels, as well as changes in calcium concentration in the cell nucleus, in regulating calcium-sensitive gene transcription. The Protocol by Shimonozo et al . provides detailed methods for detecting subcellular changes in calcium concentration. Mikoshiba and Hattori discuss the structural and functional interactions between intracellular calcium channels and channels associated with the plasma membrane. Calcium signaling is also critical to many plant responses and is the subject of the Review by Allen and Schroeder, which describes how variations in calcium oscillation and differentially localized calcium transients can encode different signals. Other ions may serve second messenger functions as well. A Perspective by Li et al . discusses the possibility that zinc released from certain classes of glutamatergic neurons may act as a trans-synaptic second messenger that enters postsynaptic neurons through various routes, such as voltage-dependent calcium channels and ionophoric glutamate receptors. Forthcoming articles will address possible roles of intracellular sodium in contributing to plastic changes in synaptic function, and in the regulation of heterotrimeric guanine nucleotide-binding protein activity. For all three classes of channels described in this Focus Issue, as well as in the articles from the STKE Archives, concrete images of ion channel function have begun to emerge from the abstract concepts of "channels" and "gating," but much remains to be determined. STKE will continue to follow the developments in this exciting field as visions of channel structure and function solidify. Featured in This Focus Issue Related Resources 1. 1.[↵][2] Ekai, called Mumon, in Zen Flesh , Zen Bones: A Collection of Zen and Pre-Zen Writings, P. Reps, N. Senzaki, Eds. (Shambhala Publications, Boston and London, 1994), The Gateless Gate, pp. 153-236. [1]: #ref-1 [2]: #xref-ref-1-1 "View reference 1. in text"